Dermatologic Toxicity of Chemotherapeutic Agents Aimee S. Payne,a William D. James,a and Raymond B. Weissb Due to its high metabolic rate, skin represents one of the major target organs of chemotherapy-associated toxicity. Reactions range from common, nonspecific exanthematous eruptions to rare but distinctive cutaneous lesions that may not become apparent until a drug transitions from clinical trials to widespread oncologic use. The challenge of the physician is to recognize reaction patterns that reflect a drug reaction, identify a likely causative drug, and determine whether the reaction is a dose-limiting toxicity. This review will focus on the cutaneous side effects of the newer classes of chemotherapy drugs, including targeted monoclonal antibody therapy and small molecule inhibitors. Semin Oncol 33:86-97 © 2006 Elsevier Inc. All rights reserved.
ince 1949 when the Food and Drug Administration approved mechlorethamine for the treatment of non–small cell lung cancer, more than 100 chemotherapeutic agents have been approved for oncologic use in the United States. Nearly half of these approvals have occurred in the last decade. Chemotherapeutic agents generally target rapidly dividing cells and consequently are toxic to organ systems with high metabolic rates, such as the hair, nails, skin, and gastrointestinal mucosa. As our knowledge of tumor biology has increased, novel therapeutic strategies have evolved, including combination chemotherapy, cytokine therapy, and more recently, biologic therapy targeted toward specific subsets of cancers. Despite these advancements, dermatologic complications continue to hinder many of the current chemotherapeutic regimens. Many excellent reviews of mucocutaneous reactions to standard chemotherapy and recombinant cytokine therapy are available (Table 1).1-3 This review will focus on the cutaneous side effect profile of nine newer chemotherapy drugs, thalidomide, and new biologic therapies for cancer.
Taxanes: Docetaxel and Paclitaxel Paclitaxel and docetaxel are members of a novel class of chemotherapeutic agents that exert anticancer activity by stabilizing microtubules. Both drugs are associated with frequent aDepartment
of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA. bLombardi Cancer Center, Georgetown University Medical Center, Washington, DC. Address correspondence to Aimee S. Payne, MD, PhD, Department of Dermatology, University of Pennsylvania, 2 Rhoades Pavilion, 3600 Spruce St, Philadelphia, PA 19104. E-mail: [email protected]
0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2005.11.004
cutaneous side effects, with an estimated incidence as high as 81%.4 Nail changes are seen in up to 41% of patients. These include hemorrhagic onycholysis, orange discoloration, subungual hyperkeratosis, transverse ridging (Beau’s lines), and acute exudative paronychia that may progress to subungual abscess5-8 (Fig 1). These findings are usually reversible after therapy is discontinued, although one case of multiple subungual abscesses with Staphylococcus aureus required antibiotics and complete nail avulsion for adequate local drainage. Another common reaction to docetaxel and paclitaxel is acral erythrodysesthesia (also known as acral erythema or hand-foot syndrome),9 consisting of paresthetic erythematous plaques on the hands and feet (Fig 2). Skin biopsies may show features of eccrine squamous syringometaplasia or neutrophilic eccrine hidradenitis, suggesting that the reaction may result from local toxicity of drug in eccrine sweat glands, which are most dense on the palms and soles.10 Cases range from mild and asymptomatic to confluent and even erosive eruptions. Reactions typically resolve within 3 to 5 weeks with prominent desquamation and often recur with subsequent courses of therapy. There are anecdotal reports on the efficacy of pyridoxine at a dose of 50 mg three times daily for treatment of palmar-plantar erythrodysesthesia due to taxane therapy,11,12 and one case of successful treatment with local hypothermia.13 Recently, a trial using a glycerin-containing Elasto-Gel thermal glove (APT, Akromed, France), which was cooled to ⫺25°C and worn on the hands just before, during, and after docetaxel infusion, was shown to significantly decrease the incidence of onycholysis, pigmentation, and acral erythrodysesthesia.14 A variety of lesions with mixed features of acral erythrodysesthesia and fixed drug eruption (FDE) have been observed in association with taxane therapy, which some have termed fixed erythrodysesthesia (Fig 3).9,15,16 FDE is
Dermatologic toxicity of chemotherapeutic agents
Table 1 Cutaneous Reaction Patterns to Chemotherapy Acral erythrodysesthesia: Painful erythematous plaques on the palms and soles, heals with prominent desquamation Cytarabine Doxorubicin 5-fluorouracil Bleomycin Lomustine Hydroxyurea Methotrexate 6-mercaptopurine Interleukin-2 Etoposide Radiation recall Reactivation of inflammatory dermatitis at a site of prior radiation therapy months to years later Methotrexate Cytarabine Dactinomycin Bleomycin Lomustine Cyclophosphamide Doxorubicin Etoposide 5-fluorouracil Hydroxyurea Melphalan Vinblastine Photosensitivity Dacarbazine 5-fluorouracil Methotrexate Mitomycin C Vinblastine
Eccrine squamous syringometaplasia Asymptomatic erythematous papules on trunk/extremities, self-limited, pathology demonstrates squamous metaplasia of eccrine gland epithelium Busulfan Carmustine Cytarabine Cisplatin Cyclophosphamide Doxorubicin Etoposide 5-fluorouracil Methotrexate Mitoxantrone Thiotepa Leg ulcers Hydroxyurea Neutrophilic eccrine hidradenitis Violaceus plaques on the trunk and extremities, asymptomatic, selflimited, pathology shows neutrophilic eccrine inflammation Cytarabine Doxorubicin Bleomycin Lomustine Chlorambucil Cyclophosphamide Mitoxantrone
Onychodystrophy/Onycholysis Bleomycin Cyclophoshamide Doxorubicin 5-fluorouracil Hydroxyurea Pigmentary changes Diffuse: Busulfan Cyclophosphamide Hydroxyurea Methotrexate Flagellate: Bleomycin Supravenous serpentine: Fotemustine Vincristine Nails: Bleomycin Cyclophosphamide Doxorubicin Hydroxyurea Teeth: Cyclophosphamide Worsening of psoriasis Interferon Interleukin-2 Sweet’s syndrome Filgrastim (G-CSF) Sargramostrin (GM-CSF)
Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.
Figure 1 Distal onycholysis.
Figure 2 Acral erythrodysesthesia.
A.S. Payne, W.D. James, and R.B. Weiss
Figure 3 Fixed erythrodysesthesia.
characterized by the appearance of a dusky patch or plaque within one to 16 hours after ingestion of the offending agent. The reaction fades with hyperpigmentation and recurs in the same location with subsequent exposures to the drug. Helper and suppressor T lymphocytes are increased in lesional skin of FDE,17 and haplotype linkages with sulfa-induced FDE have been demonstrated,18 suggesting a T-cell– based mechanism of cutaneous memory. In taxane-induced fixed erythrodysesthesia, the skin lesions appear from 1 to 14 days after exposure to the drug, may occur on first exposure to the drug, and do not always recur with subsequent therapy. These findings argue against a memory T-cell mechanism in these cases. One case of bullous FDE was attributed to a hypersensitivity reaction to paclitaxel.15 Paclitaxel was shown in early clinical trials to have a significant rate of type I hypersensitivity reactions, most commonly seen with the first two doses.19 These reactions are thought to be due to direct release of histamine and have been associated with the Cremophor EL (BASF, Ludwigshafen, Germany) vehicle used to formulate paclitaxel.20,21 Taxane therapy has also resulted in a scleroderma-like reaction, which may be partially reversible upon discontinuation of drug.9,22-24 All patients had negative serologies for connective tissue disease. Fibrosis most commonly occurs on the extremities and is preceded by an edematous phase. Some reports implicated the polysorbate-80 vehicle formulation in docetaxel-induced fibrosis, although similar findings have occurred with paclitaxel therapy, and other polysorbate-80 – containing compounds such as etoposide have not been associated with such sclerodermatous reactions. Recently, docetaxel and paclitaxel were associated with the development of subacute cutaneous lupus erythematosus in a series of four patients, confirmed by histology and direct immunofluorescence (Fig 4).25 All docetaxel recipients tested positive for anti-Ro (ss-A) antibodies, and one patient also had anti-La (ss-B) antibody, suggesting a predisposition to the development of disease. All cases resolved with discontinuation of the taxane therapy. Extravasation injury with taxanes can result in severe local
Figure 4 Drug-induced subacute cutaneous lupus erythematosus.
skin and soft tissue necrosis (reviewed separately in this journal issue) (Fig 5). One case was successfully treated with local hypothermia, oral corticosteroids, subcutaneous saline injections, and topical dimethylsulfoxide.26 There have been several reports of an extravasation recall phenomenon, where prior sites of paclitaxel extravasation or soft tissue exposure have become painful and inflamed during subsequent treatment through a different infusion site.27-29 Another recall injury prominent with taxane therapy is radiation recall, in which a site of prior ionizing radiation treatment develops an inflammatory dermatitis upon subsequent chemotherapy, with latency periods of months to years30-33 (Fig 6). The recall reaction does not always recur
Figure 5 Extravasation injury with soft tissue necrosis.
Dermatologic toxicity of chemotherapeutic agents
Anthracyclines: Polyethylene Glycol-Coated Liposomal Doxorubicin
Figure 6 Radiation recall dermatitis.
with subsequent courses of chemotherapy. Paclitaxel blocks cell division in G2 and M phases of the cell cycle during which time cells are the most susceptible to ionizing radiation injury, thereby serving as a potent radiosensitizer.34 One patient who received four irradiation sites with different skin doses reacted in only the two areas receiving the highest doses, suggesting a radiation threshold for the recall reaction.33 A distinctive pattern of hyperpigmentation has been noted with docetaxel infusion, called serpentine supravenous hyperpigmentation (Fig 7).35 Originally described with 5-fluorouracil (5-FU),36 this pattern of hyperpigmentation has subsequently been associated with a number of agents, including fotemustine,37 bromodeoxyuridine,38 vinorelbine,39 and a number of multi-agent regimens, all of which employed vincristine.40-42 Pigmentary changes typically fade over the course of months, although persistent reactions have been reported.41,43 The reaction is thought to occur due to local loss of vessel integrity and leaching of the drug into the neighboring soft tissue with possible direct effect on epidermal melanocytes.44 Most of the associated agents are known to cause prominent extravasation injury, supporting a mechanism of local tissue injury. There is one case report of toxic epidermal necrolysis after docetaxel chemotherapy.45
The anthracycline antibiotic doxorubicin directly binds DNA and is thought to cause antitumor activity through inhibition of DNA synthesis and/or induction of DNA mutagenesis and chromosomal aberrations. It is active against a broad range of solid and liquid cancers, but it has historically been associated with significant side effects, most notably due to myelosuppression and cumulative cardiac toxicity. Recently, a polyethylene glycol-coated liposomal formulation of doxorubicin has been approved for use in AIDS-related Kaposi’s sarcoma, as well as metastatic ovarian cancer refractory to paclitaxel and platinum-based chemotherapy. The new formulation allows for more selective drug accumulation in tissues with increased microvascular permeability, as would be expected in tumors with active neoangiogenesis. Although liposomal doxorubicin has been associated with a lower rate of hematologic and cardiac side effects than its nonencapsulated form, mucocutaneous toxicity still occurs and can be dose-limiting. The most common cutaneous reaction with liposomal doxorubicin is acral erythrodysesthesia, a side effect that can be dose-limiting and recurs with increasing intensity with subsequent cycles of chemotherapy. However, reported incidences of the reaction are variable, with ranges from 2% to 50% of treated patients affected.46-48 The reaction is more commonly observed with short dosing schedules or higher weekly dose intensities and appears to be related to the longer half-life of the encapsulated form.47,49 Dose comparison studies in humans suggest that dose intensities less than 40 mg/m2 may be associated with lower grades of skin toxicity.50,51 There are anecdotal reports of successful treatment measures for liposomal doxorubicinassociated acral erythrodysesthesia, including topical 99% dimethylsulfoxide four times daily,52 regional cooling,53 and oral pyridoxine with methylprednisolone.54,55 Lesions similar in clinical appearance to acral erythrodysesthesia have been observed in anatomic areas of contact
Figure 7 Serpentine supravenous hyperpigmentation.
Figure 8 Onycholysis.
pressure or microtrauma, such as the groin and axillae, sacral region, posterior elbows, inner knees and wrist folds, and have been previously described as an intertrigo-like eruption.49,56,57 Biopsies of these non-acral lesions demonstrate an interface dermatitis with vacuolar degeneration of basal keratinocytes and involvement of eccrine sweat ducts and hair follicle infundibula, with or without evidence of epidermal dysmaturation.47,56,57 These histopathologic findings make the differentiation of drug effect from graft-versus-host disease difficult, especially since the clinical distribution of lesions may be similar. Other cutaneous reaction patterns associated with liposomal doxorubicin include a mild folliculocentric scaly erythema, potentially severe and dose-limiting stomatitis, new development of melanotic macules, and sunburn/radiation recall.47,49,58
A.S. Payne, W.D. James, and R.B. Weiss with discontinuation of drug.63 Recently, gemcitabine was also associated with scleroderma-like fibrosis of the lower extremities in a patient with negative serologies.64 The fibrosis was preceded by an inflammatory edema and partially resolved after discontinuation of the gemcitabine therapy. Distinctive reactions with capecitabine (similar to its metabolite 5-FU) include nail changes such as onychomadesis (transverse ridging of the nail) and onycholysis (separation of the nail plate from the nail bed) (Fig 8).65 One patient on capecitabine therapy developed multiple periungual pyogenic granuloma-like lesions that resolved with discontinuation of chemotherapy (Fig 9).66 Also similar to 5-FU, capecitabine has also been associated with inflammation and partial clearing of actinic keratoses.67 This reaction typically occurs one to two weeks after initiation of therapy and does not require discontinuation of chemotherapy, as it can be considered a beneficial side effect. Historically, patients treated with intravenous 5-FU experienced clearing of their actinic keratoses, which subsequently led to the FDA approval of topical 5-FU for the cutaneous treatment of actinic keratoses. However, severe inflammatory reactions may require delays in subsequent courses to allow for skin healing. Radiation recall remains a relatively rare but notable reaction with both gemcitabine and capecitabine.68-71
Antimetabolites: Gemcitabine, Capecitabine, and Pemetrexed Gemcitabine (a deoxycytidine analogue with similar mechanism to cytarabine) and capecitabine (a prodrug of 5-FU) are nucleoside analogues that interfere with DNA replication. Pemetrexed is a multitargeted antifolate that depletes folate pools and inhibits de novo purine biosynthesis. Historically, antimetabolites have been associated with a number of cutaneous side effects, including radiation recall, acral erythrodysesthesia, hyperpigmentation, and nail changes. Many of the newer antimetabolic agents recapitulate these reaction patterns. Early clinical studies documented rash in up to 39% of patients receiving single-agent gemcitabine therapy, many being described as a transient macular exanthem.59,60 Gemcitabine has also been associated with recurring fixed erythrodysesthesia plaques similar to those noted with taxane therapy.61,62 Three of the four reported cases had lesions occur only in areas of lymphedema, suggesting a possible effect from localized concentration of drug. In addition, gemcitabine therapy has anecdotally resulted in a CD8⫹ CD30⫹ pseudolymphomatous reaction of the skin, which resolved
Figure 9 Periungual pyogenic granuloma.
Dermatologic toxicity of chemotherapeutic agents Gemcitabine is known to be a potent radiosensitizer, with capecitabine showing promise in this regard as well.72,73 Acral erythrodysesthesia is seen more commonly with capecitabine than with gemcitabine74,75 and occurs in more than 50% of all patients receiving capecitabine-docetaxel combination chemotherapy.76 Pemetrexed is currently approved for use in locally advanced or metastatic non–small cell lung cancer but has also undergone phase II trials for a number of other solid tumors. These studies have demonstrated that up to 100% of patients will develop some form of cutaneous toxicity, mainly described as a pruritic rash.77,78 However, most cases are mild and can be prevented or ameliorated by pretreatment with antihistamines and dexamethasone in subsequent courses of chemotherapy.77-79
Vinca Alkaloids: Vinorelbine Vinorelbine, an inhibitor of microtubule assembly approved for the treatment of non-small-cell lung cancer, demonstrates an improved safety profile over its predecessors, vincristine and vinblastine. Like other vinca alkaloids, local and potentially severe skin necrosis occurs with extravasation injury and may be treated with local hyaluronidase and saline injections.80 Acral erythrodysesthesia was noted in four of 60 patients undergoing single-agent continuous high-dose infusion with vinorelbine for metastatic breast cancer.81 There is one case report of serpentine supravenous hyperpigmentation with vinorelbine therapy.39
Topoisomerase I Inhibitors: Topotecan and Irinotecan Topotecan and irinotecan are novel chemotherapeutic agents that are approved for use alone and in combination for a variety of tumors refractory to standard chemotherapy regimens. Most cutaneous reactions are mild to moderate in severity, self-limiting, and do not require any specific treatment. A morbilliform rash occurs in 6% to 21% of patients receiving topotecan or irinotecan monotherapy.82-84 One case of neutrophilic eccrine hidradenitis recurring with subsequent doses of topotecan has been reported.85 In addition, topotecan therapy has been associated with a cellulitis-like fixed drug eruption which decreased in severity with continued therapy.86
Thalidomide Thalidomide was approved in 1998 for the cutaneous treatment of moderate to severe erythema nodosum leprosum. It was originally introduced in Europe in 1956 as a sedative for the treatment of insomnia and pregnancy-associated nausea.87 It was subsequently withdrawn from the market in 1961 when its severe teratogenic side effects were realized. In the mid 1960s an Israeli dermatologist using thalidomide for its hypnosedative effects in leprosy patients made the serendipitous discovery that patients with a reactive form of lep-
91 rosy known as erythema nodosum leprosum experienced rapid resolution of their skin lesions with thalidomide. Since that time, many studies have uncovered roles for thalidomide as an anti-inflammatory, immunomodulatory, and anti-angiogenic agent.88,89 Thalidomide is currently approved for treatment of myeloma and under experimental evaluation for the treatment of a variety of autoimmune and neoplastic disorders, including malignant gliomas, renal cell carcinoma, prostate and colorectal carcinoma, Kaposi’s sarcoma, acute myelogenous leukemia, lupus, sarcoidosis, and graft-versushost disease, among others.90 From a cutaneous perspective, thalidomide is generally well tolerated. Dry skin and rash are the most frequent skin toxicities, with morphologies including morbilliform, maculopapular, and erythrodermic. The onset of rash can be as late as four months after initiating therapy. The incidence of rash ranges from 14% to 46%, with most cases not requiring discontinuation of therapy.91,92 However, there are some notable exceptions to these cases. In patients infected with the human immunodeficiency virus (HIV), three of eight patients (37.5%) experienced a severe hypersensitivity reaction requiring discontinuation of treatment.93 HIV-infected patients are well known to have a higher incidence of hypersensitivity reactions from a number of drug classes, such as sulfa and penicillin.94 Additionally, Hall et al summarized four historical and two new cases of exfoliative erythroderma and/or toxic epidermal necrolysis (TEN) associated with thalidomide therapy.91 In three cases, patients had recently started other medicines associated with TEN such as allopurinol or trimethoprim/ sulfamethoxazole. However, discontinuation of all medicines and subsequent rechallenge with thalidomide resulted in worsening or recurrence of the skin rash. These findings are supported by a randomized clinical trial of thalidomide in patients with TEN, which demonstrated a marked increase in mortality in the thalidomide-treated group versus placebotreated controls (10/12 v 3/10 deaths).95 Interestingly, patients simultaneously treated with thalidomide and dexamethasone appear to have more severe skin reactions than patients treated with thalidomide alone.91,96 More detailed studies are needed to determine the biologic and clinical significance of these findings.
Monoclonal Antibody Therapy: Rituximab and Trastuzumab Monoclonal antibody therapies directed against specific pathophysiologic molecular targets have entered the chemotherapeutic armamentarium within the last decade, beginning with the approval of rituximab (a chimeric anti-CD20 monoclonal antibody) for B-cell non-Hodgkin’s lymphoma in 1997. The majority of the monoclonal antibody therapies are typically well tolerated from a cutaneous perspective, although one case of Stevens-Johnson syndrome has been associated with rituximab therapy.97 Reported adverse cutaneous events include infusion reactions and serum sickness. Infusion reactions, consisting of fever, headache, hypoten-
92 sion, shortness of breath, morbilliform rash, and asthenia are relatively frequent with rituximab and trastuzumab, an antiHER2 chimeric monoclonal antibody approved for use in HER2⫹ breast cancer.98 These reactions occur within 1 to 2 days of the first infusion of drug and are thought to be secondary to the rapid release of cytokines as antibodies bind to circulating antigen-expressing cells. In rare cases, tumor lysis syndrome with bronchospasm, hypoxia, and even death may occur. Serum sickness, consisting of fever, arthralgias, and morbilliform rash often with acral accentuation, typically occurs 1 to 2 weeks after infusion and is associated with laboratory evidence of complement activation (depressed C3 and C4 levels) and tissue inflammation (elevated erythrocyte sedimentation rate and C-reactive protein). Two cases have been associated with rituximab therapy, and in one patient, antibodies to the mouse F(ab=)2 fragments of rituximab were identified.99,100 Both patients responded to pulse methylprednisolone therapy with resolution of symptoms within 48 hours. Serum sickness results from tissue deposition of circulating antigen-antibody complexes and theoretically would be predicted to occur with any of the chimeric antibody therapies. However, phase II clinical trials detected the presence of antibodies to rituximab in only three of greater than 300 patients treated, all of whom were asymptomatic,101 and there have been no reports of serum sickness events with other more widely used chimeric antibody therapies such as abciximab for coronary artery disease or infliximab for treatment of rheumatoid arthritis and Crohn’s disease.
Small Molecule Signal Transduction Inhibitors: Imatinib Mesylate Imatinib mesylate is a small molecule inhibitor of signal transduction through the abl, platelet-derived growth factor receptor, and c-kit tyrosine kinases. It is approved for use in Philadelphia chromosome–positive chronic myelogenous leukemia and malignant gastrointestinal stromal tumors. A diverse pattern of cutaneous adverse events has been reported with use of imatinib. In initial clinical trials, rash was reported in 22% of patients undergoing treatment, and up to 60% of patients demonstrated edema, which was often prominent in the periorbital region.102-104 The frequency of rash is dose-dependent, with an incidence of 33% at doses less than 400 mg daily, increasing to 93% at daily doses of 600 mg or higher.105 The most common morphology is an exanthematous macular and papular eruption. However, severe reactions including Stevens-Johnson syndrome have been linked to higher initial doses of imatinib therapy.106,107 Although skin reactions may be extensive, cutaneous desensitization appears possible. Several patients including one case of Stevens-Johnson syndrome have been effectively managed with a 2-day to 2-week discontinuation of imatinib followed by reintroduction at a lower daily dose in combination with oral prednisolone.107,108 One successful reintroduction regimen involved an initial 100 mg daily dose with
A.S. Payne, W.D. James, and R.B. Weiss
Figure 10 Acute generalized exanthematous pustulosis.
weekly 100-mg dose escalations, without adjunctive use of oral corticosteroids. Additionally, one patient with exfoliative dermatitis had complete resolution of her rash when she was decreased to a once-weekly dosing regimen.109 Acute generalized exanthematous pustulosis (AGEP), consisting of high fever, leukocytosis, and a sterile follicular pustular eruption, has been associated with imatinib therapy.110,111 One case began in the intertriginous regions and spread to involve the trunk and later the extremities, similar to what is observed in cases of mercury poisoning,112 while other cases initially presented on the face and neck (Fig 10). Other authors have described an exfoliative dermatitis with fever and nonfollicular pustules.105 Biopsies have demonstrated parakeratosis, keratinocyte necrosis, and intraepidermal collections of neutrophils, supporting a diagnosis of AGEP over pustular psoriasis. The rash generally resolves within two weeks, although in some cases the reaction was considered severe enough to warrant discontinuation of imatinib therapy. Sweet’s syndrome (acute febrile neutrophilic dermatosis), classically consisting of fever, leukocytosis, and an acute onset of erythematous plaques characterized histologically by a dense dermal infiltrate of neutrophils, has been described in patients with chronic myelogenous leukemia after imatinib mesylate monotherapy.113,114 In one case, the rash resolved with oral corticosteroid therapy and did not recur with reini-
Dermatologic toxicity of chemotherapeutic agents
Figure 11 Acneiform eruption associated with gefitinib.
tiation of imatinib, while in another case, recurrent skin lesions consistent with Sweet’s were observed with subsequent imatinib treatments. Taken together, the reports of AGEP and Sweet’s syndrome suggest that imatinib may be associated with an increased incidence of neutrophilic dermatoses that may not require discontinuation of therapy after the acute reaction has resolved. Photosensitization has been described in a series of eight patients, all of whom were negative for antinuclear antibodies.115 In a prospective study of 54 patients treated with imatinib, four (7%) demonstrated photosensitivity.105 Interestingly, a number of patients have noted pigmentary changes while undergoing treatment, including hypopigmentation and/or hyperpigmentation, as well as darkening of the hair.105,116,117 As the c-kit receptor is known to play a role in melanogenesis and melanocyte homeostasis,118 the photosensitivity and pigmentary changes may represent direct physiologic responses to imatinib by skin melanocytes. Anecdotal miscellaneous reactions have been reported in association with imatinib therapy, including small vessel vasculitis, erythema nodosum, and graft-versus-host–like rash.119
93 trunk, and extremities, sparing the palms and soles. Scaling of the interfollicular skin may also be present. Biopsies of lesions show prominent keratin plugging in dilated infundibula of hair follicles, with or without a dense neutrophilic folliculitis.126,130 One case reported a complete absence of the follicular epithelial lining.129 These reports are in agreement with mouse models of EGF inhibition, in which follicular inflammation with alopecia has been observed.131,132 The efficacy of treatments for the rash is variable, with some reactions spontaneously clearing despite continued therapy with EGF pathway inhibitors, and inconsistent response to typical acne treatments including topical benzoyl peroxide, topical retinoids, and topical or oral antibiotics. The appearance of the rash is not a contraindication to continued therapy. In the case of cetuximab, two studies have demonstrated a positive correlation between severity of the acneiform rash and overall response and survival.127,133 Paronychial inflammation (often with pyogenic granulomalike lesions) (Fig 12) is another common cutaneous reaction with EGF receptor blockade.124,126,134 Lesions may demonstrate S aureus on culture and may be treated with topical antibiotics, topical corticosteroids, and/or electrodessication for larger lesions. Other reported reaction patterns with the EGF pathway inhibitors include acral xerosis with desquamation, small aphthous ulcerations of the oral and nasal mucosa, and urticaria.124,126 Additionally, there is one report of a necrolytic migratory erythema-like rash that responded to withdrawal of gefitinib therapy.135
Proteasome Inhibitors: Bortezomib This agent is the first of a new class of antineoplastic drugs that inhibit intracellular protein degradation pathways. Bortezomib is a dipeptidyl boronic acid inhibitor with high specificity for the proteasome and is currently approved for the treatment of multiple myeloma. In early phase I/II trials, cu-
Epidermal Growth Factor Pathway Inhibitors: Gefitinib and Cetuximab Gefitinib is a small molecule inhibitor of epidermal growth factor (EGF) signal transduction approved for use in advanced non-small cell lung cancer. Cetuximab is a chimeric anti-EGF receptor monoclonal antibody recently approved for use in advanced colorectal cancers. A notable reaction pattern with the EGF pathway inhibitors is a diffuse acneiform rash, noted in up to two thirds of patients receiving therapy (Fig 11).120-127 Reactions, consisting of erythematous follicular-based papules and pustules with or without comedones,128,129 are often dose-dependent and begin 1 week after initiation of treatment. Lesions typically occur on the face,
Figure 12 Paronychial inflammation after cetuximab therapy.
A.S. Payne, W.D. James, and R.B. Weiss
Table 2 Reaction Patterns of Newer Chemotherapeutic Agents Paclitaxel/docetaxel Oncholysis, onychodystrophy Paronychia, subungual abscess Acral erythrodysesthesia Fixed erythrodysesthesia Sclerodermatous Subacute cutaneous lupus erythematosus Extravasation injury Radiation recall Serpentine supravenous hyperpigmentation Toxic epidermal necrolysis Liposomal doxorubicin Acral erythrodysesthesia Intertrigo-like eruption Folliculocentric scaly erythema Stomatitis UV/radiaton recall Increased melanotic macules Gemcitabine Macular exanthema Fixed erythrodysesthesia Pseudolymphoma Radiation recall Sclerodermatous Capecitabine Onychomadesis, onycholysis Periungual pyogenic granulomas Radiation recall Acral erythrodysesthesia Inflammation of actinic keratoses Pemetrexed Maculopapular exanthema Vinorelbine Extravasation injury Acral erythrodysesthesia Serpentine supravenous hyperpigmentation
taneous toxicity was mild, with 8% to 15% of patients demonstrating skin reactions, described as a maculopapular or desquamative rash.136,137 However, one patient undergoing treatment with bortezomib for multiple myeloma developed a purpuric rash during the second cycle of therapy,138 with skin biopsy demonstrating leukocytoclastic vasculitis. The skin lesions responded to oral corticosteroids but recurred with subsequent cycles of bortezomib.
Conclusions A summary of cutaneous reactions associated with the newer chemotherapy agents is presented in Table 2. The differential diagnosis of a cutaneous reaction in a cancer patient receiving chemotherapy includes a broad range of etiologies other than chemotherapy drug reaction, including infection, graft-versus-host disease, paraneoplastic syndromes, metastatic spread of primary tumor, and nutritional deficiencies. With the advent of multiagent chemotherapy regimens, drug reactions have become increasingly difficult to attribute to a single agent, especially since multiple agents may be associated
Topotecan/irinotecan Morbilliform eruption Neutrophilic eccrine hidradentis Fixed drug eruption Thalidomide Xerosis Morbilliform/erythrodermic Toxic epidermal necrolysis Rituximab Stevens-Johnson syndrome Infusion reaction Serum sickness Trastuzumab Infusion reaction Imatinib mesylate Edema, especially periorbital Stevens-Johnson syndrome Acute generalized exanthematous pustulosis Sweet’s syndrome Photosensitivity Hypopigmentation Gefitinib/cetuximab Acneiform rash Acral xerosis and desquamation Paronychial inflammation Mucosal aphthous ulcers Necrolytic migratory erythema Bortezomib Maculopapular exanthema Leukocytoclastic vasculitis
with a given cutaneous reaction pattern. Often these diagnostic uncertainties can only be clarified with rechallenge, and it is the responsibility of the evaluating physician to determine whether rechallenge is medically permissible. Many chemotherapy skin reactions are mild to moderate and do not require alteration of a patient’s chemotherapy protocol. However, certain reactions can be considered dose-limiting, including Stevens-Johnson syndrome/toxic epidermal necrolysis and the more severe and/or persistent sclerodermoid and acral erythrodysesthesia reactions. Interestingly, in the case of imatinib, even severe cutaneous reactions such as Stevens-Johnson syndrome have been effectively managed with decreased dosing regimens. However, these reactions should not be taken lightly because the skin represents the body’s physical barrier against external injury and infection, and compromise of this barrier in an immunocompromised cancer patient may be fatal. Accurate diagnosis relies on the physician’s knowledge of the most commonly reported cutaneous reaction patterns with a particular chemotherapeutic agent, and conversely, familiarity with the scope of other drugs that can cause a particular cutaneous reaction pattern.
Dermatologic toxicity of chemotherapeutic agents
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