INTRODUCTION — Systemic and local treatments for cancer can cause a number of changes in the skin, mucous membranes, hair, and nails [1-6]. When dermatologic lesions arise in patients being treated for cancer, they may represent a side effect of therapy, but other etiologies need to be considered. These include a cutaneous reaction to other drugs, exacerbation of a previously existing condition, infection, metastatic tumor involvement, a paraneoplastic phenomenon, graft-versus-host disease, or a nutritional disorder.

Accurate diagnosis and management of chemotherapy-related side effects require the clinician to be knowledgeable of the most commonly reported cutaneous reaction patterns for the drugs the patient is receiving. The clinician must also be familiar with the cutaneous manifestations of certain cancers, as well as the dermatologic effects of other forms of cancer treatments. In some cases, diagnostic uncertainty can only be clarified with a rechallenge, and the clinician must determine whether rechallenge is safe and medically justifiable.

The cutaneous adverse effects of conventional cytotoxic cancer therapy agents are presented here. Other mucocutaneous complications of cancer treatment are discussed separately.

●(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

●(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

●(See "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".)

●(See "Alopecia related to systemic cancer therapy".)

●(See "Oral toxicity associated with systemic anticancer therapy".)

IMMUNE-MEDIATED INFUSION REACTIONS — Virtually all chemotherapeutic agents have the potential to initiate an infusion reaction when administered systemically, although few are immune mediated. Various types of skin eruptions can accompany infusion reactions, which may take the form of an anaphylactic reaction or a mild "standard infusion reaction." Infusion reactions to specific chemotherapy agents and issues related to prophylaxis and management are discussed separately. (See "Infusion reactions to systemic chemotherapy".)

The following is a brief synopsis of the types of immune-mediated hypersensitivity reactions that can either directly or indirectly affect the skin and mucous membranes, and their clinical manifestations.

●Most infusion reactions with the platinum drugs (cisplatin, carboplatin, and oxaliplatin) are classic type I immunoglobulin E (IgE)-mediated allergic reactions (table 1). Urticaria, pruritus, angioedema, and other symptoms of anaphylaxis typically develop within one hour of drug administration, although such reactions may occur up to 24 hours following exposure.

●Type III reactions result from formation and tissue deposition of antigen-antibody complexes. Type III reactions may be responsible for the cutaneous vasculitis seen with methotrexate [7,8] and the serum sickness-like reaction following infusion of rituximab. (See "Serum sickness and serum sickness-like reactions" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

●Type IV reactions are mediated by activated T cells. Contact dermatitis to topical mechlorethamine (nitrogen mustard) is an example of a classic type IV allergic reaction to a chemotherapy agent [9-11]. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

Other immune-mediated mechanisms that are incompletely understood are thought to underlie Stevens-Johnson syndrome/toxic epidermal necrolysis and certain allergic exanthematous drug rashes. (See 'Diffuse erythema and exfoliative dermatitis' below and 'Stevens-Johnson syndrome/toxic epidermal necrolysis' below.)

PIGMENTARY CHANGES — Pigmentary changes involving the skin, nails, and mucous membranes are common in patients receiving cytotoxic drugs, particularly alkylating agents and antitumor antibiotics (table 2) [12]. The area of enhanced pigmentation may be localized or more diffuse, and it may affect the skin, mucous membranes, hair, and/or nails. The pigmentary changes usually resolve with drug discontinuation but may persist. As an example, the rare gingival margin hyperpigmentation seen with cyclophosphamide is usually permanent.

Pigmentary changes may be diffuse or localized.

Fluoropyrimidines — Fluorouracil is one of the most ubiquitous drugs used in the treatment of malignancy. It is often associated with a hyperpigmentation reaction that may affect the skin diffusely or locally (in sun-exposed areas), in a serpentine manner (a pigmentary pattern that follows an underlying vein proximal to an infusion site), darken the nail beds, and induce mucosal pigmentation of the tongue and conjunctiva. Topical fluorouracil can induce hyperpigmentation in treated areas. The fluorouracil derivative tegafur can induce well-circumscribed, brown to black, macular pigmentation that appears on the palms, soles, nails, and glans penis; the localization in these cases is unexplained. Hyperpigmentation associated with fluorouracil usually resolves within weeks to several months after cessation of therapy; however, in certain cases, nail hyperpigmentation may persist for years [13-17].

Other drugs

Diffuse reaction — In addition to fluorouracil, many systemic medications induce pigmentary reaction patterns that affect the skin in a diffuse manner. As examples:

●Busulfan causes a generalized skin darkening (the so-called "busulfan tan") that can mimic the cutaneous manifestations of Addison's disease. Although busulfan can also cause adrenal insufficiency, the skin pigmentary change is thought instead to be secondary to a toxic effect on melanocytes [18,19]. Features that can help to distinguish cutaneous busulfan toxicity from true Addison's disease include normal levels of melanocyte-stimulating hormone and adrenocorticotropic hormone (ACTH). (See "Clinical manifestations of adrenal insufficiency in adults".)

●Pegylated liposomal doxorubicin can induce a macular hyperpigmentation over the trunk and extremities, including the palms and soles [20]. This reaction has not been described with unencapsulated doxorubicin.

●Hyperpigmentation due to hydroxyurea may affect the face, neck, lower arms, palms, and nails; pigmentation can also be accentuated in areas of pressure or trauma [21,22]. This pressure-induced hyperpigmentation is also reported for cisplatin [23].

●Methotrexate can rarely induce a diffuse, brown skin hyperpigmentation [24].

●Procarbazine has been associated with generalized melanosis [25].

Local — Local changes in skin pigmentation may be associated with intrinsic, anatomic features of the skin (eg, mucous membranes, skin creases, flexural or intertriginous areas, palms or soles, and face). However, a suspected local drug reaction may be due to other extrinsic factors that act in combination with the drug. In addition to fluorouracil, other examples include thiotepa, ifosfamide, and docetaxel (sites of adhesive placement on the skin); cisplatin, hydroxyurea, and bleomycin (sites of trauma or pressure); and daunorubicin (sun-exposed areas) [1,26]. The local hyperpigmentation seen in areas of skin exposed to adhesive may reflect secretion of the drug in sweat.

Some of these reactions may represent postinflammatory hyperpigmentation rather than a local effect of the drug itself, especially if administration of the agent is associated with trauma, skin irritation, or a local allergic reaction (ie, contact dermatitis).

The following are examples of local chemotherapy-induced hyperpigmentation:

●The pigmentary changes caused by bleomycin, cyclophosphamide, busulfan, and doxorubicin have a predilection for flexural areas and palmar creases. Ifosfamide hyperpigmentation can occur in flexural areas, dorsal and plantar surfaces of the feet, extensor surfaces of fingers and toes, on the scrotum, and occasionally on large areas of the trunk; it may also occur under occlusive dressings.

●Mitoxantrone hyperpigmentation can affect the face, dorsum of the hands, and nails.

●Daunorubicin may induce annular or polycyclic pigmentation of the scalp [1].

●Mucosal hyperpigmentation has been associated with busulfan, cyclophosphamide (gingiva), tegafur (lower lip as well as glans penis), doxorubicin (tongue and buccal mucosa), and cisplatin [1] as well as fluorouracil.

●Like topical fluorouracil, topical mechlorethamine can induce hyperpigmentation in treated areas.

Serpentine, flagellate, and reticular hyperpigmentation — Serpentine hyperpigmentation describes a supravenous pigmentary pattern that follows the course of an underlying vein proximal to an infusion site. This phenomenon is most commonly seen with fluorouracil but has also been associated with fotemustine, vincristine, vinorelbine, and docetaxel [4].

Serpentine hyperpigmentation has also been reported with some combination regimens, such as CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) for lymphoma treatment [27,28].

Linear (flagellate) hyperpigmentation (picture 1) may be seen with bleomycin [29,30]. Multiple linear, erythematous or hyperpigmented streaks arise at sites of scratching or other minor traumas to the skin. Generalized pruritus is common and may precede the eruption.

Paclitaxel, cytarabine, fluorouracil, and idarubicin may induce a reticular hyperpigmentation predominantly located on the trunk and lower extremities [31,32]. Pruritus is often an accompanying symptom.

Hair — In addition to causing alopecia, chemotherapy can also cause pigmentary changes in hair. (See "Alopecia related to systemic cancer therapy".)

●Both cisplatin and cyclophosphamide can induce hair color change; with cyclophosphamide, the range is from light red to black.

●Methotrexate may induce hyperpigmentation of scalp hair, eyebrow hair, and eyelashes; this tends to occur in bands that alternate with the normal color, a feature known as the "flag sign" [33]. This results from alternating periods of treatment and no treatment.

●One man receiving therapy with bleomycin, doxorubicin, and vincristine experienced hair color change from black to red [1].

NAIL DISORDERS — Nonspecific nail changes are commonly observed during the course of systemic cancer treatment [34]. They include transverse grooves on the nail plate (Beau's lines) and onychomadesis (shedding of the nail), due to prolonged inactivation of the nail matrix (picture 2A-B). Fingernails grow approximately 0.1 mm per day; thus, the distance of a Beau's line from the proximal nail fold gives an approximate indication of when the acute insult occurred. (See "Overview of nail disorders", section on 'Transverse grooves (Beau lines)'.)

Cytotoxic chemotherapeutic agents have also been associated with pigmentary changes (chromonychia) and onycholysis, a detachment of the nail plate from the nail bed. Other inflammatory reaction patterns involving the nail folds include pyogenic granuloma and acute exudative paronychia that may progress to subungual abscess.

The various nail disorders that are associated with individual chemotherapy agents are summarized in the table (table 3), and some are described below. After discontinuation of chemotherapy, all of these conditions generally resolve as the nail grows out.

Pigmentary changes — Medications may induce diffuse hyperpigmentation or banding/streaking of the nail plate (melanonychia striata) or bed. Besides fluorouracil, a wide range of agents have been implicated, including alkylating agents, taxanes, antimetabolites (hydroxyurea, cyclophosphamide), anthracyclines, and antitumor antibiotics, among others (table 3) [1,34]. Melanonychia appears one to two months after the initiation of chemotherapy and may be associated with cutaneous and mucosal hyperpigmentations. Taxanes may also induce a red nail discoloration, due to subungual hemorrhages, and true leukonychia (picture 3) [35]. Leukonychia is also observed in patients treated with doxorubicin, cyclophosphamide, and vincristine [36].

Onycholysis — Onycholysis is caused by inflammation in the nail bed, which leads to detachment of the overlying nail. The cytotoxic drugs most frequently associated with onycholysis are the taxanes paclitaxel and docetaxel (picture 4) [4]. Other medications that have been reported to cause onycholysis include cyclophosphamide, doxorubicin, etoposide, fluorouracil, hydroxyurea, capecitabine, ixabepilone, and the combination of bleomycin plus vinblastine [1,37].

An intriguing association between denervation and protection from chemotherapy-induced nail changes was suggested in a report of a patient with a complete right arm nerve palsy due to advanced breast cancer who developed docetaxel-related nail changes in all extremities except the paretic hand [38].

A systematic review of 12 studies supports the pretreatment prophylactic use of frozen gloves and frozen socks for the prevention of taxane-induced nail and skin toxic effects [39]. However, the included studies were generally small and showed considerable methodologic heterogeneity regarding the cooling protocols, chemotherapy regimens, and choice of control limbs. Discomfort from cold may be reduced, without changes in efficacy, by using frozen gloves prepared at a temperature of -10 to -20°C rather than at the standard temperature of -25 to -30°C [40].

A drawback of cold therapy may be a reduced exposure of the extremity to the therapeutic agent, which in theory may permit persistence of metastatic tumor cells in that location. Thus, the use of cold therapy to mitigate skin and nail toxicity must be decided on a case-by-case basis.

Inflammatory changes — A number of infectious and noninfectious inflammatory changes of the nail folds and nail bed have been reported.

●Painful paronychial inflammation, often associated with pyogenic granulomas, may be induced by etoposide, capecitabine, methotrexate, and doxorubicin. (See "Paronychia" and "Pyogenic granuloma (lobular capillary hemangioma)".)

●Treatment with docetaxel and paclitaxel may induce an exudative paronychia with or without progression to frank abscess [4].

PHOTOSENSITIVITY — An increased sensitivity to ultraviolet (UV) light exposure (photosensitivity) has been associated with a variety of chemotherapy agents [1,41-43].

Photosensitivity reactions can be manifested in a variety of ways:

●A phototoxic reaction, which is characterized by the onset of severe erythema within minutes to hours following light exposure. These reactions are not immunologically mediated, and they usually spare sun-protected areas. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)

●A photoallergic reaction, which is a type IV hypersensitivity reaction (table 1) that develops at least 24 hours after light exposure. Photoallergic reactions may spread to involve non-sun-exposed areas and usually cause dermatitis rather than erythema. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)

●Photorecall phenomenon (also called UV reactivation reaction or solar burn reactivation reaction), in which the administration of a chemotherapy drug (typically methotrexate but also taxanes) in the absence of light can trigger a sunburn-like reaction in the same distribution as a sunburn that the patient may have sustained months to years before [44-46].

●In contrast, a photoenhancement reaction can occur when patients who receive a drug (typically high-dose methotrexate) within two to five days of exposure to UV light develop severe erythema within the sun-exposed areas.

●Photo-onycholysis, in which a drug-mediated reaction to light leads to separation of the nail bed from the nail plate, most commonly affecting the distal nail.

Phototoxic reactions — A phototoxic reaction resembles an exaggerated sunburn, with erythema, edema, pain, and tenderness in sun-exposed areas, such as the face, the "V" area of the upper chest, and the dorsa of the hands. In severe cases, blistering can occur. Postinflammatory hyperpigmentation is common. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)

The clinical diagnosis is based upon the distribution of the eruption (ie, a sharp demarcation between sun-exposed versus protected sites) (picture 5A-B) and the temporal relationship to administration of the offending agent. If the diagnosis is in doubt, photo patch testing can be used as adjunctive diagnostic measures [1].

The pathogenesis of phototoxic chemotherapy reactions is thought to involve concentration of the drug within the skin and subsequent absorption of UV light, resulting in apoptosis of keratinocytes. On biopsy, the characteristic histologic findings include dyskeratotic keratinocytes, a vacuolar interface dermatitis, and papillary dermal edema with minimal inflammation [47].

Treatment of phototoxic reactions involves discontinuation of the offending agent and avoidance of direct exposure to sunlight through the use of protective clothing and a topical sunscreen for at least two weeks. Physical sunscreens containing titanium oxide or zinc oxide are preferred because chemical sunscreens, especially oxybenzone, can be associated with photoallergic reactions (see "Selection of sunscreen and sun-protective measures"). Symptomatic treatment with cool compresses and topical steroids may be helpful. Severe cases may require systemic steroids.

Patients receiving photosensitizing drugs should be counseled regarding the risk of adverse reactions to sunlight and encouraged to use UV protection with sunscreens and protective clothing.

Photoallergic reactions — In contrast to phototoxic reactions, a photoallergic reaction is characterized by pruritus rather than burning, with a papulovesicular eruption, erythema, and/or scaling over sun-exposed areas. Photosensitivity reactions to flutamide (an antiandrogen) and ftorafur (also called tegafur, a prodrug of fluorouracil) are typically photoallergic rather than phototoxic [41,48,49]. Symptoms generally clear within four to eight weeks after drug discontinuation.

Photorecall and photoenhancement — Methotrexate can cause a phototoxic recall reaction (UV reactivation reaction or solar burn reactivation) in which drug administration in the absence of light triggers a sunburn-like reaction in the same distribution as a sunburn that the patient may have sustained months or years earlier [50-52]. Symptoms are usually reproduced with rechallenge.

High-dose methotrexate is also associated with photoenhancement reactions, in which drug administration within two to five days after exposure to UV light causes severe erythema in sun-exposed areas. Leucovorin rescue is ineffective at preventing these reactions. In contrast to photoreactivation, retreatment with methotrexate usually does not reproduce this reaction. (See "Therapeutic use and toxicity of high-dose methotrexate".)

There are isolated reports of a similar photoenhancement phenomenon with taxanes, gemcitabine, pegylated liposomal doxorubicin, and some combination cytotoxic regimen [45,53-56].

Photo-onycholysis — Photo-onycholysis is a unique adverse light reaction caused by the combination of certain chemotherapeutic agents (eg, mercaptopurine) with UV light [57-59]. Separation of the nail bed from the nail plate most commonly affects the distal nail and occurs two to four weeks after drug administration.

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS AND SCLERODERMA-LIKE CHANGES — Subacute cutaneous lupus erythematosus (SCLE), manifested by annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 6A-B), has been reported following taxanes [60-62], fluorouracil and capecitabine [63], doxorubicin plus cyclophosphamide [64], and gemcitabine [65]. While phototoxicity may play a role in initiating or sustaining active SCLE, the pathogenesis also involves autoimmunity. This is supported by the presence of deposits of immunoglobulin G (IgG) and complement components on epidermal keratinocytes, immunohistopathologic findings that are identical to those found in idiopathic disease. Another shared feature of drug-induced and idiopathic SCLE is the presence of anti-Ro/SSA antibodies in a majority of cases. (See "Overview of cutaneous lupus erythematosus", section on 'Subacute cutaneous lupus erythematosus'.)

Scleroderma-like changes, consisting of edema, tightening, and induration of the skin on the trunk and extremities, have been reported in patients treated with bleomycin [66], gemcitabine [67], and docetaxel [68]. The serologic workup for scleroderma was negative in these five patients, and the changes resolved following discontinuation of the drug. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

RADIATION RECALL AND ENHANCEMENT

Radiation recall dermatitis — Radiation recall dermatitis (RRD) is an inflammatory skin reaction that develops in an area of previously irradiated skin after administration of certain promoting agents; most cases have been associated with chemotherapy [69]. There may be a long interval between the administration of the causative agent and the appearance of RRD. The frequency of these reactions is unclear; in one study, RRD occurred in 8 of 91 patients (9 percent) who received chemotherapy following radiation therapy [70]. (See "Radiation dermatitis", section on 'Radiation recall reaction'.)

RRD was originally described with dactinomycin [71]. Since then, a number of other drugs have also been associated with this phenomenon (table 4), particularly anthracyclines and anthracycline-like drugs [72-75].  

Erythema, which may be painful, is the most common sign [76,77]. Vesiculation, desquamation, and ulceration have also been reported [1]. Histologically, epidermal dysplasia, necrotic keratinocytes, and a mixed inflammatory reaction [78] characterize involved areas, with some cases showing psoriasiform dermatitis. Additional dermal changes include fibrosis, vasodilatation, and atypical fibroblasts. Many of these findings mimic the histologic findings of acute, severe sunburn or radiation dermatitis.

RRD typically occurs with the first dose of the chemotherapy agent or combination. Drug dose appears to be an important factor, as evidenced by one report in which the patient initially received doxorubicin 27 mg/m² two weeks after radiation therapy with no reaction; administration of a higher drug dose 12 days later resulted in RRD [79].

In addition, RRD may also require a minimum threshold radiation dose. In two case reports, patients receiving various doses of radiotherapy with bleomycin or docetaxel had a radiation recall reaction only in those skin sites that had received the highest radiation dose [80,81].

Chemotherapy agents administered by the intravenous (IV) route usually produce RRD more rapidly (range, several minutes to 14 days) than oral agents, which have a longer lag period (range, three days to two months) [82,83]. The duration of symptoms also differs with drugs administered intravenously or orally. RRD caused by IV administration usually resolves within two weeks, whereas symptoms caused by orally administered medications may last for several months [84].

The pathogenesis of RRD is controversial. An idiosyncratic hypersensitivity reaction has been proposed, with the "trauma" of prior radiation therapy sensitizing an area of skin into manifesting an immune reaction when there is little or no systemic activation (akin to the Koebner phenomenon) [74]. However, the occurrence of many of these reactions after the first drug exposure argues against an immune mechanism, and defects in DNA repair [85] as well as toxic drug effects [74] have also been proposed as causative factors.

Dose reduction and the use of corticosteroids have been used as adjunctive measures to prevent recurrence of RRD, although rechallenge with the same agent does not always lead to symptom recurrence [86].

Radiation enhancement — Enhancement of the dermatologic toxicity of radiation therapy can occur if a radiosensitizing chemotherapy drug is administered concurrently or within one week of radiation therapy [1]. The drugs that have been associated with radiation enhancement (also called radiation sensitizers) are listed in the table (table 4).

The synergistic interaction between chemotherapy and radiation is exploited clinically in situations in which concurrent chemotherapy and radiation are administered to enhance antitumor effect (eg, concomitant fluorouracil and radiation therapy for many gastrointestinal tumors). Since the target of the radiation beam is typically located deep within the body, enhanced skin toxicity is usually not a significant problem. Skin toxicity is seen more commonly with more superficial radiation fields. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)

Radiation enhancement involving the skin resembles RRD, with painful erythema, edema, superficial desquamation, and, if severe, erosions (wet desquamation). Similar to RRD, the eruption usually localizes to the irradiated field, but there may be local extension to unirradiated areas. Histologically, epidermal dysplasia, necrotic keratinocytes, and a mixed inflammatory reaction characterize involved areas, with some cases showing psoriasiform dermatitis [78]. (See "Radiation dermatitis".)

Susceptibility to this effect decreases as the time between administration of chemotherapy and radiation therapy lengthens. In one report, superficial desquamation occurred in 50 percent of patients with lung cancer who received doxorubicin within five days of radiation therapy, while no desquamative reactions occurred when the interval between radiation and chemotherapy was increased to three weeks [87,88].

Possible explanations for the radiation-sensitizing effect of some chemotherapy drugs include increased blood supply and cellular reoxygenation to the tissue, interference with repair of radiation damage, competition for repair enzymes, and an increased percentage of cells in sensitive phases of the cell cycle [89]. For example, paclitaxel arrests cell division in the G2 and M phases of the cell cycle, when cells are the most susceptible to ionizing radiation injury [90].

The eruption is usually self-limiting, resolving over a period of days to months. Treatment of radiation enhancement reactions is symptomatic and includes the application of cold compresses, local wound care to prevent infection, and the avoidance of trauma, irritation, heat, and ultraviolet (UV) light. Long-term sequelae may include skin atrophy, fibrosis, and telangiectasias. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)

HAND-FOOT SYNDROME (ACRAL ERYTHEMA) — Hand-foot syndrome (HFS) has been known by a variety of terms including acral erythema, palmar-plantar erythrodysesthesia, toxic erythema of the palms and soles, Burgdorf's reaction, and toxic erythema of chemotherapy [91]. Since the original report in patients receiving high-dose cytarabine for acute leukemia, HFS has been described most often in patients receiving cytarabine, pegylated liposomal doxorubicin (PLD), capecitabine, or fluorouracil, although many other drugs have been implicated (table 5) [91-96].

Capecitabine toxicity may be associated with genetic polymorphisms of dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS), two enzymes that are involved in the metabolism of capecitabine and other fluoropyrimidines [97]. Although genetic tests are available that sequence the entire DPYD gene and identify some TYMS polymorphisms that predispose to excess hematologic and gastrointestinal toxicity, genetic testing is not considered standard of care prior to initiating fluoropyrimidine therapy. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Testing for DPYD and TYMS variants'.)

Multitargeted tyrosine kinase inhibitors, such as sorafenib, sunitinib, and others that target angiogenesis, are associated with a high incidence of a hand-foot skin reaction, but the clinical and histologic patterns differ from the classic HFS that develops with conventional cytotoxic agents. This subject is discussed in detail elsewhere. (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

Clinical presentation — Affected patients initially complain of a tingling sensation in the palms and/or soles. This is followed by edema and tender, symmetrical erythema, which is most pronounced over the fat pads of the distal phalanges (picture 7A-B). Skip areas may occur, as can extension to the dorsal surfaces of the extremities.

Although rare, HFS involving the penis and scrotum has been reported [98]. An intertriginous form, named malignant intertrigo, that involves the axillary, antecubital, inframammary, and inguinal folds and the buttocks, similar to symmetric drug-related intertriginous and flexural exanthema, has also been reported [99,100]. (See "Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural reaction pattern'.)

Affected areas may develop pallor, blistering, and desquamation [101-103]. A particularly severe bullous variant, progressing to full-thickness epidermal necrosis and sloughing, has been reported following cytarabine or high-dose methotrexate, particularly in children [104-109].

HFS is a painful condition, and it may limit daily activities such as walking or grasping objects. Functional impairment is a component of the grading system for severity of HFS (table 6).

A presumed variant of HFS, termed fixed erythrodysesthesia plaque (FEP), is characteristic of intravenous (IV) injections of docetaxel [110,111]. This lesion 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 an area of hyperpigmented skin five to six weeks later.

Fingerprint loss — One potential consequence of capecitabine-associated HFS is the loss of fingerprints [112-114]. Patients on long-term therapy should be advised of this potential adverse effect, since it may be an impediment in situations in which fingerprint identification is necessary (eg, international travel).

However, an important point is that fingerprint loss is not permanent. In a prospective cohort study of 66 patients who were undergoing treatment with capecitabine or a tyrosine kinase inhibitor and who were fingerprinted at baseline, within 6 to 10 weeks after treatment initiation, and after treatment discontinuation, nine patients (14 percent) had severe loss of fingerprints; loss was unrelated to severity of HFS [115]. Complete recovery of fingerprints occurred in all three patients who were able to participate in post-treatment assessments within two to four weeks after treatment discontinuation.

Risk factors — At least in the case of cytarabine, capecitabine, and doxorubicin, HFS is dose related. Furthermore, drug formulation and administration schedules that result in sustained serum levels of cytotoxic agents are more frequently associated with HFS, as evidenced by the following examples:

●The liposome-encapsulated form of doxorubicin (pegylated liposomal doxorubicin [PLD]) is associated with a higher incidence of HFS than the nonencapsulated form, particularly when initial doses greater than 40 mg/m² are administered [116].

●While HFS is uncommon when fluorouracil is administered as a bolus injection, it is often the dose-limiting toxicity with prolonged infusions [117].

●The incidence of HFS with capecitabine (an oral fluoropyrimidine that is converted in vivo to fluorouracil, providing prolonged tissue exposure) is nearly 60 percent [118].

Histopathology and pathogenesis — The histologic changes of HFS are nonspecific. A vacuolar interface dermatitis with necrotic keratinocytes is most commonly seen, with superficial dermal edema and a perivascular lymphocytic infiltrate [119,120]. The pathologic differential diagnosis includes graft-versus-host disease (GVHD, in the appropriate clinical setting) and Stevens-Johnson syndrome (SJS). The distinction of HFS from GVHD and SJS is important since the treatments are distinct. Unfortunately, a biopsy may not be able to distinguish between these entities in a clinically relevant timeframe. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Skin' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Histopathology'.)

The pathogenesis of HFS is not well understood. A direct toxic effect of the chemotherapeutic agent on eccrine coils (which are in highest density on the palms and soles) is most often proposed, although there is no direct evidence to support this theory, and microscopic evidence of damage to the eccrine sweat glands or ducts is only infrequently reported [121,122].

Others suggest that HFS represents a mild form of acute GVHD, although evidence to substantiate this viewpoint is lacking. Furthermore, HFS most often develops in patients who have neither undergone hematopoietic cell transplantation nor received blood products [1]. Finally, the occasional co-occurrence of facial erythema/edema, papular rash, and fever has led some to view this as a type I (immunoglobulin E [IgE]-mediated) allergic reaction [123].

For patients treated with capecitabine, at least some data suggest that expression of the capecitabine-activating enzyme thymidine phosphorylase is significantly greater in the skin of the palms as compared with skin on the lower back, providing higher tissue levels of the active moiety to this area [119]. Furthermore, the proliferative rate of epidermal basal cells in the palm was also higher as compared with skin from the back, suggesting that palmar skin might be more sensitive to the local action of cytotoxic drugs.

Treatment — The main treatment for HFS is drug interruption or dose modification. Supportive treatment includes topical corticosteroids to decrease inflammation, wound care for erosions and ulcerations to prevent infection, emollients and topical keratolytics to decrease hyperkeratosis, and analgesics for pain control [91].

HFS usually resolves within two to four weeks after discontinuation of the causative agent, but healing frequently involves superficial desquamation of involved areas. There are usually no long-term sequelae, although palmoplantar keratoderma may develop as a result of long-standing HFS [124].

For patients who develop severe (grade 3 (table 6)) HFS, subsequent chemotherapy doses should be reduced to avoid recurrence. Based upon the severity of the reaction, the hazard of rechallenge, and the clinical situation, it may be necessary to discontinue therapy entirely and switch to an alternative regimen, if one is available.

Prevention

Topical urea — For patients receiving capecitabine chemotherapy, we suggest topical urea 10% cream for the prevention of HFS. The topical urea cream is applied to hands and feet three times per day and should be reapplied after washing hands. At low concentrations (2 to 10%), topical urea acts as a humectant that increases the hydration of the stratum corneum and is generally well tolerated. The prophylactic benefit of topical urea treatment has not been demonstrated for other chemotherapy agents; however, given the low risk for toxic effects, a therapeutic trial is reasonable for patients at risk of developing HFS with other drugs.

The efficacy of topical urea with or without lactic acid for the prevention of HFS has been addressed in a few randomized trials with conflicting results:

●In a randomized trial, a topical urea/lactic acid-based topical preparation applied twice daily for 21 days was compared with an emollient cream for the prevention of HFS in 137 patients receiving capecitabine for colon, lung, or breast cancer [125]. More patients in the topical urea/lactic acid group than in the placebo group developed HFS (40 versus 30 percent). The severity of HFS was similar in the two groups.

●In a subsequent randomized trial, topical urea 10% cream three times daily for six weeks was compared with a topical emollient preparation containing antioxidants for the prevention of HFS in 152 patients treated with capecitabine for gastrointestinal or breast cancer [126]. HFS was less common in patients treated with topical urea cream than in those treated with the antioxidant preparation (22 versus 40 percent). The severity of HFS was similar in the two groups.

Pyridoxine — Early studies suggesting symptomatic improvement from pyridoxine in patients with HFS [127,128] led to interest in the use of this vitamin as a preventive agent. However, in four separate phase III trials in which patients receiving capecitabine-based chemotherapy or PLD were randomly assigned to either pyridoxine (150 or 200 mg daily) or placebo, pyridoxine did not prevent this complication, lessen its severity, or permit higher doses of chemotherapy to be administered [129-132]. In addition, pyridoxine did not ameliorate symptoms among placebo-treated patients who received open-label pyridoxine after the development of grade 2 or 3 HFS [129].

Whether higher daily doses of pyridoxine might confer greater protection against HFS is uncertain. One randomized trial comparing 300 mg pyridoxine daily versus no treatment in 56 patients receiving capecitabine did not reveal any improvement in grade 2 or worse HFS with pyridoxine [133]. In contrast, another trial comparing 400 versus 200 mg of pyridoxine daily in 56 patients receiving capecitabine noted a significant reduction in HFS with the higher dose (relative risk 0.55, 95% CI 0.33-0.92) [134].

Two meta-analyses concluded that there was inadequate evidence to make any recommendation about using pyridoxine (at any dose) for prevention of chemotherapy-induced HFS [135,136]. Until further information becomes available, we suggest not using pyridoxine therapy to prevent HFS.

Celecoxib — In a 2014 meta-analysis of randomized trials (140 patients), oral celecoxib 200 to 400 mg twice daily for 12 to 18 weeks significantly decreased the risk of moderate to severe (grades 2 and 3) HFS (odds ratio 0.37, 95% CI 0.19-0.71) [136]. However, celecoxib is known for its potential cardiovascular adverse effects with long-term use and upper gastrointestinal risk of bleeding. In our view, the benefit-to-risk ratio is not favorable when considering the use of celecoxib for prevention of HFS. (See "NSAIDs: Adverse cardiovascular effects".)

Other approaches — Support for a variety of other approaches to treat or prevent HFS comes from small case series, although none has been proven in randomized trials:

●Local application of cold during therapy by applying ice packs to the wrists and ankles may help by decreasing blood flow to the hands and feet [137,138].

●A benefit for oral corticosteroids in reducing the frequency of HFS was suggested by two small series [139,140].

NEUTROPHILIC ECCRINE HIDRADENITIS — Neutrophilic eccrine hidradenitis (NEH) is a reactive disorder that may occur in association with malignancy (with or without chemotherapy), infections, and certain medications. The original description of drug-induced NEH was in a patient receiving cytarabine for acute myeloid leukemia [141]. Since then, a variety of chemotherapeutic agents have been associated with this entity (table 7) [1,142,143]. In addition, NEH has been reported in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), after acetaminophen use, as a paraneoplastic eruption in patients with malignancy who are not receiving chemotherapy (probably as a variant of Sweet syndrome), and as an idiopathic condition in children. (See "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis' and "Cutaneous manifestations of internal malignancy", section on 'Sweet syndrome'.)

Patients present with the eruption one to two weeks after therapy with the offending agent. The clinical presentation is nonspecific. Lesions are typically asymptomatic, erythematous, edematous plaques but may be purpuric and painful. They can be located on the extremities (picture 8A), trunk, and face (picture 8B), including the periorbital region, where severe lesions may mimic cellulitis. Generalized, erythema multiforme-like lesions have been reported [144]. (See "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis'.)

In all cases of suspected NEH, a biopsy should be performed since the clinical picture is nonspecific, while the histopathologic presentation is distinct. In most cases, neutrophils surround the eccrine glands, and a vacuolar interface dermatitis is visible in glands and ducts, along with necrosis of lining cells [145]. Epidermal keratinocyte atypia is a common associated finding in cases that are related to chemotherapy administration [146].

If chemotherapy-induced neutropenia is present, neutrophils may be absent on histologic examination. However, other characteristic findings, such as eccrine gland necrosis, are still identifiable [1].

The natural history is that of spontaneous resolution in one to two weeks [147]. While the reaction is self-limited and resolves without therapy, some studies support the use of systemic corticosteroids [148]. However, efficacy has not been established in randomized trials [148]. One case report suggests that oral dapsone may be useful for prophylaxis [149]. The majority of patients with NEH will develop the same eruption with rechallenge.

The cause of NEH in patients receiving chemotherapy is unknown. It is postulated that a high concentration of the drug in sweat has a direct toxic effect on the eccrine glands [145,150].

EXANTHEMATOUS (MACULOPAPULAR) ERUPTIONS — A wide variety of chemotherapy drugs have been associated with a mild, nonspecific, exanthematous drug eruption, including bortezomib, lenalidomide, cladribine, fludarabine, gemcitabine, pemetrexed, and cytarabine. Lesions may be "morbilliform" or may consist of a profuse eruption of small, erythematous papules showing no resemblance to any infective exanthem. Morbilliform eruptions (picture 9A-B) are characterized by monomorphic, erythematous papules and are usually classified as "drug rash" in the United States prescribing information and literature references. The similarity of these rashes to those described for many other drugs underscores the importance of evaluating all medications taken by the patient before concluding that the rash is caused by the chemotherapy agent. (See "Exanthematous (maculopapular) drug eruption".)

Adverse skin reactions with bortezomib may include an erythematous, papular rash or erythematous nodules or plaques [68,151]. In one study, rash affected 26 of 140 patients (19 percent), in most cases during the third or fourth course of therapy [152]. Six patients underwent biopsy, which showed a small vessel necrotizing vasculitis. A morbilliform eruption occurs in approximately 30 percent of patients treated with lenalidomide [153]. The risk of rash appears to be independent from dose or whether lenalidomide is combined with dexamethasone or not. Lenalidomide has also been associated with Stevens-Johnson syndrome/toxic epidermal necrolysis (table 8) [154-156]. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Immunomodulatory drugs'.)

The management of patients with a chemotherapy drug rash is dictated by the severity of the reaction as well as the clinical circumstances surrounding the use of the individual chemotherapy agent. Pertinent issues include whether the offending agent is being used with curative versus palliative intent and whether an adequate substitute from another drug class is available. In mild cases, treatment with topical steroids is usually recommended, without specific modification of the chemotherapy regimen.

Pretreatment with corticosteroids is not usually recommended to prevent or diminish a chemotherapy-induced drug rash. One exception to this general rule is the drug pemetrexed, a folate analog used in the treatment of mesothelioma and non-small cell lung cancer. In an early phase II study, pemetrexed was associated with a papular skin rash in 66 percent of treated patients [157]. The rash was sometimes associated with edema and/or desquamation and responsive to corticosteroid treatment.

Subsequent phase I, II, and III trials have noted a much lower incidence (less than 20 percent) and severity of skin rash, attributed to the routine use of dexamethasone 4 mg twice daily for three days starting the day before treatment [158-161]. As a result, premedication with this schedule of dexamethasone has become a standard practice for patients receiving pemetrexed [159]. Whether fewer doses would suffice is unknown.  

At least one case of urticarial vasculitis has been attributed to pemetrexed [162]. Conjunctivitis, periorbital edema, and lower extremity edema and erythema have also been reported in patients treated with pemetrexed [163,164]. (See "Ocular side effects of systemically administered chemotherapy".)

FIXED DRUG ERUPTIONS — Fixed drug eruptions are typically characterized by the rapid formation of a solitary macule, plaque, or bulla after drug exposure in a sensitized individual, although multiple or diffuse lesions can be observed in rare cases. The cytotoxic drugs most commonly associated with a fixed drug eruption are listed in the table (table 9). (See "Fixed drug eruption".)

The characteristic early lesion is a sharply demarcated, erythematous, round to oval macule, which develops from 30 minutes to 8 hours after drug exposure and arises in the same location after each exposure (picture 10A-B). One-half occur on the oral or genital mucosa (picture 10D). Within hours, the lesion becomes edematous, forming a plaque, which may evolve to bulla (picture 10C) and eventually to erosion. Lesions persist if the drug is continued, but they resolve within days to weeks after the drug is discontinued.

Postinflammatory hyperpigmentation may take months to resolve. No specific treatments are recommended other than discontinuation of the offending drug, although topical steroids instituted early after lesion development may help to reduce postinflammatory hyperpigmentation.

DIFFUSE ERYTHEMA AND EXFOLIATIVE DERMATITIS — Diffuse erythema has been described with hydroxyurea, busulfan, and cladribine [165]. Many of these eruptions are mild and self-limited, and they do not proceed to exfoliation. Drugs that are more likely to be associated with exfoliative dermatitis include cisplatin, methotrexate, and, rarely, intravesical mitomycin [166-169]. At least some of these cases are thought to be immune mediated.

SEVERE CUTANEOUS DRUG REACTIONS — A number of antineoplastic agents may cause life-threatening cutaneous adverse reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) [170].

Whether chemotherapy agents cause erythema multiforme, an immune-mediated reaction induced in most cases by infections and infrequently by drugs, remains uncertain. Similarities in clinical and histopathologic findings between SJS and erythema multiforme (ie, presence of targetoid lesions and keratinocyte necrosis) may have led to a misclassification of limited SJS as erythema multiforme in the few published cases [171]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Stevens-Johnson syndrome/toxic epidermal necrolysis — SJS/TEN is a serious and potentially fatal mucocutaneous drug reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis. Its severity is related to the percentage of body surface area involved, ranging from less than 10 percent in SJS to greater than 30 percent in TEN.

Several anticancer agents have been associated with SJS/TEN (table 10) [170]. Determining the drug causality in cancer patients may be difficult, due to the frequent use of multiple chemotherapy agents in combination and the concurrent use of other drugs to treat underlying conditions and comorbidities. In addition, cancer patients may have an increased risk of SJS/TEN due to the malignancy itself [172].

Although the pathogenetic mechanisms of SJS/TEN are incompletely understood, it is now accepted that drug-specific CD8⁺ cytotoxic T cells, along with natural killer (NK) cells, are major inducers of keratinocyte apoptosis [173]. Among the various cytotoxic proteins and cytokines (eg, soluble Fas ligand, perforin/granzyme, tumor necrosis factor-alpha) involved in the extensive keratinocyte apoptosis, granulysin, a cytolytic protein found in cytotoxic T cells and NK cells, appears to play a key role [174].

SJS/TEN begins with a prodrome of fever and influenza-like symptoms followed in one to three days by an eruption of ill-defined, coalescing, erythematous macules with atypical target lesions (picture 11). As the disease progresses, vesicles and bullae form, and within days the skin begins to slough (picture 12). Mucosal involvement occurs in over 90 percent of cases.

Acute complications may include massive loss of fluids and electrolyte imbalance, hypovolemic shock, sepsis, and multiple organ dysfunction. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Most patients with SJS/TEN require inpatient management, often in a burn unit, because of extensive skin detachment and subsequent risk for hyponatremic dehydration and sepsis. Immediate and permanent discontinuation of the offending agent is warranted. Patients who develop SJS/TEN should never be re-exposed to the causative drug because of the risk of a fatal recurrence. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

Drug reaction with eosinophilia and systemic symptoms — DRESS is a rare and potentially life-threatening, drug-induced hypersensitivity reaction that presents with a skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and/or internal organ involvement (liver, kidney, lung). A few antineoplastic agents have been associated with DRESS, including chlorambucil [175] and lenalidomide [176].

In most patients, the reaction begins two to six weeks after the initiation of the offending medication. The eruption starts as a morbilliform eruption that progresses more or less rapidly to a diffuse, confluent, and infiltrated erythema (picture 13A-B). Liver involvement occurs in 60 to 80 percent of patients. Identification and prompt withdrawal of the offending drug is the mainstay of treatment for patients with DRESS. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

MISCELLANEOUS REACTIONS — Treatment-induced leg ulcers occasionally occur in patients taking long-term hydroxyurea for myeloproliferative disorders [177-180]. Lesions are most commonly located near the malleoli and are characteristically painful. The primary mechanism of ulcer formation may involve hydroxyurea-induced inhibition of the synthesis (S) phase of the cell cycle, leading to basal keratinocyte damage and the suppression of collagen synthesis. Discontinuation of therapy is necessary for healing; ulcers recur if treatment is reinitiated [180].

Whether leg ulcers are more frequent in patients receiving hydroxyurea for sickle cell disease is unclear. Issues related to use of hydroxyurea in this setting are discussed in detail elsewhere. (See "Hydroxyurea use in sickle cell disease".)

There are many other rare cutaneous reactions that have been attributed to chemotherapy agents, including Sjögren's syndrome, dermatomyositis, Raynaud's phenomenon, reactivation of varicella-zoster infection, porphyria, and a blistering disorder characterized as a paraneoplastic pemphigus-like phenomenon with fludarabine [1]. (See "Paraneoplastic pemphigus".)

A partial list of such reactions and the associated chemotherapeutic agents can be found in the following table (table 11).

SUMMARY AND RECOMMENDATIONS

●Systemic and local application of conventional cytotoxic chemotherapy agents in patients with cancer can cause a number of changes in the skin, mucous membranes, hair, and nails. Some of these changes are immune-mediated hypersensitivity reactions, including urticaria and angioedema, exanthematous eruptions, vasculitis, or contact dermatitis (table 1). (See 'Immune-mediated infusion reactions' above.)

●Pigmentary changes involving the skin, nails, and mucous membranes are common in patients receiving cytotoxic drugs, particularly alkylating agents and antitumor antibiotics (table 2). The hyperpigmentation can be localized or diffuse, sometimes with distinctive patterns, such as serpentine or flagellate (picture 1). (See 'Pigmentary changes' above.)

●Nail changes, such as hyperpigmentation and onycholysis (picture 4), sometimes associated with inflammatory involvement of the periungual tissues, may be induced by many medications, including alkylating agents, taxanes, antimetabolites, anthracyclines, and antitumor antibiotics (table 3). (See 'Nail disorders' above.)

●Photosensitivity reactions, including photoallergic and phototoxic reactions (picture 5A), have been associated with a variety of chemotherapy agents. Photorecall and photoenhancement reactions have been reported with methotrexate and taxanes. The combination of some agents, such as mercaptopurine, with ultraviolet light may induce photo-onycholysis. (See 'Photosensitivity' above.)

●Subacute cutaneous lupus erythematosus, manifested by annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 6A-B), has been reported in a few cases following docetaxel, fluorouracil, or capecitabine. (See 'Subacute cutaneous lupus erythematosus and scleroderma-like changes' above.)

●Radiation recall dermatitis (RRD) is an inflammatory skin reaction that develops in an area of previously irradiated skin after administration of several chemotherapy agents (table 4). Some drugs may enhance the efficacy and dermatologic toxicity of radiation therapy when administered concurrently or within one week of radiation therapy. They are referred to as radiation sensitizers. This synergistic interaction may be exploited clinically in situations where chemotherapy and radiation therapy are administered together to enhance the therapeutic effect. (See 'Radiation recall dermatitis' above and 'Radiation enhancement' above.)

●Hand-foot syndrome (HFS), also called acral erythema (picture 7A-B), occurs most often in patients receiving cytarabine, pegylated liposomal doxorubicin, capecitabine, or fluorouracil, although many other drugs have been implicated (table 5). In patients who will be treated with capecitabine, we suggest initiating topical application of topical urea 10% cream for the prevention of HFS (Grade 2B). Given the low risk for toxic effects, a therapeutic trial is reasonable for those who develop moderate to severe HFS with other drugs (Grade 2C). HFS is dose related and usually resolves within two to four weeks after discontinuation of the causative agent with superficial desquamation of involved areas.

●Neutrophilic eccrine hidradenitis presents with erythematous, edematous plaques (picture 8A-B) in patients with malignancy (with or without chemotherapy), infections, or receiving a variety of chemotherapeutic agents (table 7). (See 'Neutrophilic eccrine hidradenitis' above and "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis'.)

●Exanthematous eruptions, including morbilliform rashes (picture 9A-B) and fixed drug eruptions (picture 10A-D), may occur in association with many chemotherapeutic agents (table 9). (See 'Exanthematous (maculopapular) eruptions' above and 'Fixed drug eruptions' above.)

●A number of antineoplastic agents (table 10) may cause severe cutaneous reactions, such as Steven-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) (picture 13A-B). SJS/TEN is a rare, life-threatening cutaneous reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis (picture 12). Patients who develop SJS/TEN or DRESS should never be re-exposed to the causative drug because of the risk of a fatal recurrence. (See 'Severe cutaneous drug reactions' above.)

●Rare reactions, including leg ulcers, Sjögren syndrome, dermatomyositis, Raynaud phenomenon, reactivation of varicella-zoster infection, porphyria, and a paraneoplastic pemphigus-like phenomenon, have been associated with several chemotherapeutic agents (table 11). (See 'Miscellaneous reactions' above.)