Cutaneous adverse effects of conventional chemotherapy agents

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 an adverse 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.

The accurate diagnosis and management of chemotherapy-related side effects requires the clinician to be knowledgeable about the most common 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 a rechallenge with a lower dose, if appropriate, 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. Infusion reactions are also 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".)

●(See "Mucocutaneous toxicities associated with immune checkpoint inhibitors".)

●(See "Infusion reactions to systemic chemotherapy".)

TOXIC ERYTHEMA OF CHEMOTHERAPY — The term "toxic erythema of chemotherapy" (TEC) was proposed in 2008 as a unifying, descriptive, diagnostic entity for the various clinical and histopathologic reaction patterns with significant overlapping features reported with chemotherapy [7]. The most frequently seen clinical presentation involves the hands and feet, hence the name "hand-foot syndrome" (HFS), which has been known by a variety of terms including acral erythema, palmar-plantar erythrodysesthesia, palmar-plantar erythema, toxic acral erythema, toxic erythema of the palms and soles, Burgdorf's reaction, and periarticular thenar erythema and onycholysis (PATEO syndrome) [8].

Originally reported in patients receiving high-dose cytarabine for acute leukemia, HFS has been frequently described in patients receiving pegylated liposomal doxorubicin (PLD), capecitabine (an oral fluoropyrimidine that is converted in vivo to fluorouracil, providing prolonged tissue exposure), or fluorouracil, although many other drugs have been implicated (table 1) [8-13].

Multitargeted tyrosine kinase inhibitors, such as sorafenib, sunitinib, and other kinase inhibitors 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. Hand-foot skin reaction is discussed in detail elsewhere. (See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

Frequency and risk factors — TEC occurs in approximately 6 to over 60 percent of patients treated with the chemotherapeutic agents most frequently implicated (eg, doxorubicin, PLD, fluoropyrimidines [fluorouracil, capecitabine], cytarabine, docetaxel), depending on the specific agent, dose, and mode of administration [8,14]. At least in the case of cytarabine, capecitabine, and doxorubicin, TEC is dose related. Drug formulations and administration schedules that result in sustained serum levels over time are more frequently associated with TEC.

As an example, PLD is associated with a higher frequency of TEC than the nonencapsulated form of doxorubicin, particularly with initial doses greater than 40 mg/m² [15]. TEC is often the dose-limiting toxicity with certain chemotherapeutic agents, such as capecitabine [16].

Pathogenesis — The pathogenesis of TEC 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) has been proposed. However, there is no direct evidence to support this theory, as microscopic evidence of damage to the eccrine sweat glands or ducts is only infrequently reported [17,18].

TEC 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, though TEC is often delayed by two to three weeks following chemotherapy rather than within 24 hours (as is usually seen with type I reactions) [19].

For patients treated with capecitabine, at least some data suggest that expression of the capecitabine-activating enzyme thymidine phosphorylase (TYMP) is significantly greater in the skin of the palms compared with skin on the lower back, providing higher tissue levels of the active moiety to this area [20]. Furthermore, the proliferative rate of epidermal basal cells in the palm was also higher compared with skin from the back, suggesting that palmar skin might be more sensitive to the local action of cytotoxic drugs.

Fluoropyrimidine toxicity may be associated with genetic polymorphisms of dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS), genes that encode for two enzymes that are involved in metabolism [21]. 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 (at least in North America). (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Testing for DPYD and TYMS variants'.)

Histopathology — The histologic changes of TEC are nonspecific. A vacuolar interface dermatitis with basilar squamatization and necrotic keratinocytes is most commonly seen, with superficial, dermal edema and a mild, perivascular, lymphocytic infiltrate [14,22]. Epidermal dysmaturation resembling squamous cell carcinoma in situ may be observed [23]. In addition, changes to the adnexal structures, including vacuolar changes in the epithelium, neutrophilic infiltration or necrosis of eccrine glands, or squamous syringometaplasia, have also been described [24-26].

The pathologic differential diagnosis includes graft-versus-host disease (in the appropriate clinical setting) and Stevens-Johnson syndrome (SJS). The distinction of TEC from graft-versus-host disease and SJS is important since the treatments are distinct. Unfortunately, a biopsy may not be able to distinguish among 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'.)

Clinical presentation

Hand-foot syndrome — When TEC affects the hands and feet (hand-foot syndrome [HFS]), it is most pronounced over the fat pads of the distal phalanges (picture 1A-B). Affected patients initially complain of a tingling sensation, which is followed by edema and tender, symmetric erythema. Skip areas may occur, as can extension to the dorsal surfaces of the extremities. Symptoms of TEC often develop one to three weeks after chemotherapy administration but may occur sooner, often within five to seven days with capecitabine.

Affected areas may develop pallor, blistering, and desquamation [27-29]. A particularly severe bullous variant resembling SJS/toxic epidermal necrolysis (TEN), progressing to full-thickness epidermal necrosis and sloughing, has been reported following cytarabine or high-dose methotrexate, particularly in children [30-35].

TEC 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 2).

Clinical variants — TEC may also occur in intertriginous sites (previously known as malignant intertrigo) with involvement of the axillary folds, antecubital/popliteal fossae, neck, inguinal folds, buttocks, and genitals, mimicking a symmetric drug-related intertriginous and flexural exanthema [36-38] (see "Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural reaction pattern'). Involvement of the ears is commonly seen with cytarabine, giving rise to the phrase "Ara-C (cytarabine) ears."

PATEO syndrome, a variant of TEC, was originally described in 2003 as HFS associated with taxanes (paclitaxel, docetaxel) that is accentuated over the dorsum of the hands (particularly the hypothenar eminence) or base of the thumb [39]. Distinct nail changes, including onycholysis, can occur due to cytotoxicity to the nail matrix. PATEO syndrome can additionally affect the skin around the Achilles tendon. (See 'Onycholysis' below.)

Another presumed variant of TEC, termed "fixed erythrodysesthesia plaque," is characteristic of intravenous injections of docetaxel [40-42]. 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 TEC is the loss of fingerprints [43-46]. 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 [46]. Loss was unrelated to the severity of TEC in this study. 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.

Diagnosis — The diagnosis of TEC is usually clinical, based on medication history and clinical presentation. A skin biopsy is not routinely performed.

Treatment — The main treatment for TEC is drug interruption or dose modification, depending on the severity of the reaction. Supportive treatment includes topical corticosteroids, wound care for erosions and ulcerations, emollients and topical keratolytics for hyperkeratotic areas, and analgesics for pain control [8].

TEC usually resolves with superficial desquamation of involved areas within two to four weeks after discontinuation of the causative agent. There are usually no long-term sequelae, although palmoplantar keratoderma may develop as a result of longstanding TEC [47].

For patients who develop severe (grade 2 or 3 [depending on the drug] (table 2)) 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.

A small, phase 2A trial (21 patients) found that topical heparin (1000 international units/g) applied four times daily to the hands and feet of patients with grade ≤2 capecitabine-induced HFS reduced HFS severity by at least 1 grade in 90 percent of patients, with a median response time of three weeks [48]. However, these findings need to be confirmed in larger studies.

Prevention

●Topical urea – In patients who will be treated with capecitabine, the local application of a topical urea 10% cream may help prevent HFS. The urea-based 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. Urea up to 30% acts as an emollient and keratolytic, with urea greater than 30% functioning mostly as a keratolytic. These higher concentrations can be useful in instances of chronic reactions that lead to skin thickening [49]. 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 evaluated in a few randomized trials and meta-analyses with conflicting results. Moreover, as the included studies included a variety of interventions as comparators but not vehicle, the benefit of urea cream versus emollient cream remains uncertain:

•A 2022 meta-analysis of four randomized trials found that prophylactic treatment with urea was associated with a reduced risk of developing grade 2 or higher HFS or hand-foot skin reaction (odds ratio [OR] 0.62, 95% CI 0.49-0.79). However, subgroup analysis of only HFS demonstrated reduced risk of all-grade HFS (OR 0.44, 95% CI 0.22-0.90) but not grade 2 or higher HFS (OR 0.78, 95% CI 0.29-2.09) [50].

•A meta-analysis of three trials of prophylactic urea cream for capecitabine-induced HFS did not find it effective in reducing the risk of all-grade HFS (risk ratio [RR] 0.81, 95% CI 0.52-1.26) as well grade 2 or greater HFS (RR 0.74, 95% CI 0.41-1.32) [51].

●Pyridoxine – Early studies suggesting symptomatic improvement from pyridoxine in patients with HFS led to interest in the use of this vitamin as a preventive agent [52,53]. However, in four separate phase 3 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 [54-57]. Whether higher daily doses of pyridoxine might confer greater protection against HFS is uncertain [58,59]. The results of three meta-analyses suggest that there is inadequate evidence to make any recommendation about using pyridoxine (at any dose) for prevention of chemotherapy-induced HFS [50,60,61].

●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 all-grade and grade ≥2 HFS (OR 0.37, 95% CI 0.19-0.71; and OR 0.47, 95% CI 0.29-0.78, respectively) [61]. These results were confirmed in a 2022 meta-analysis [50].

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 the prevention of HFS. (See "NSAIDs: Adverse cardiovascular effects".)

●Other – Other treatments that have been used in a limited number of patients include regional cooling (not indicated for drugs administered as continuous infusion) [62,63], antiperspirants [64], topical sildenafil [65], topical silymarin [66], and other herbal products [67]. However, none of these treatments has been evaluated in high-quality studies.

NEUTROPHILIC ECCRINE HIDRADENITIS — Neutrophilic eccrine hidradenitis (NEH) is a reactive, self-limited disorder that may occur in association with malignancy (with or without chemotherapy), infections, and certain medications [68]. (See "Neutrophilic dermatoses", section on 'Neutrophilic eccrine hidradenitis'.)

The original description of drug-induced NEH was in a patient receiving cytarabine for acute myeloid leukemia [69]. Since then, a variety of chemotherapeutic agents have been associated with this entity that may be considered within the spectrum of toxic erythema of chemotherapy (TEC) (table 3) [1,70,71]. However, the cause of NEH in patients receiving chemotherapy remains elusive. It is postulated that a high concentration of the drug in sweat has a direct toxic effect on the eccrine glands [24,72]:

●Clinical presentation – 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 2A), trunk, and face (picture 2B), including the periorbital region, where severe lesions may mimic cellulitis. Generalized, erythema multiforme-like lesions have been reported [73].

●Diagnosis – Because the clinical picture is nonspecific, a biopsy should be performed in cases of suspected NEH to confirm the diagnosis. Histopathologic examination shows neutrophils surrounding the eccrine glands, vacuolar degeneration in glands and ducts, along with necrosis of lining cells, and squamous syringometaplasia of eccrine ducts [24]. Epidermal keratinocyte atypia is a common associated finding [25]. 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].

●Management – The natural history is that of spontaneous resolution in one to two weeks [74]. While the reaction is self-limited and resolves without therapy, some studies support the use of systemic corticosteroids [75]. However, efficacy has not been established in randomized trials [75]. One case report suggests that oral dapsone may be useful for prophylaxis [76]. The majority of patients with NEH will develop the same eruption with rechallenge.

PHOTOSENSITIVITY REACTIONS — An increased sensitivity to ultraviolet (UV) light exposure (photosensitivity) has been associated with a variety of chemotherapy agents [1,77-80]. Photosensitivity reactions can be manifested in a variety of ways, including phototoxic reaction, photoallergic reaction, photorecall, and photoenhancement.

Phototoxic reactions — A phototoxic reaction is a nonimmunologically mediated reaction that 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. Severe erythema develops within minutes to hours following light exposure. Postinflammatory hyperpigmentation is common. The most common chemotherapeutic agent associated with phototoxic reactions is methotrexate [80]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)

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. Characteristic histologic findings include dyskeratotic keratinocytes, a vacuolar interface dermatitis, and papillary dermal edema with minimal inflammation [81].

The clinical diagnosis is based upon the distribution of the eruption (ie, a sharp demarcation between sun-exposed versus protected sites) (picture 3A-B) and the temporal relationship to the administration of the offending agent. If the diagnosis is in doubt, photo patch testing can be used as adjunctive diagnostic measures [1].

The treatment of phototoxic reactions involves the 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 — Photoallergic reactions are type IV, delayed hypersensitivity reactions that develop at least 24 hours after light exposure. In contrast to phototoxic reactions, a photoallergic reaction is characterized by a pruritic, papulovesicular eruption that involves sun-exposed areas but may spread to non-sun-exposed areas. Photosensitivity reactions to flutamide (an antiandrogen) and ftorafur (also called tegafur, a prodrug of fluorouracil) are typically photoallergic rather than phototoxic [77,82,83]. Symptoms generally clear within four to eight weeks after drug discontinuation. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Photoallergy'.)

Photorecall and photoenhancement — A photorecall phenomenon (also called "UV reactivation reaction" or "solar burn reactivation reaction") occurs when the administration of a chemotherapy drug (typically methotrexate but also taxanes) triggers a sunburn-like reaction in the absence of light exposure in the same distribution as a sunburn that the patient may have sustained months to years before [84-88]. Symptoms are usually reproduced with rechallenge.

In contrast, photoenhancement occurs 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. In contrast to photoreactivation, retreatment with methotrexate does not usually reproduce this reaction. (See "Therapeutic use and toxicity of high-dose methotrexate".)

There are isolated reports of a photoenhancement phenomenon with taxanes, gemcitabine, pegylated liposomal doxorubicin (PLD), and some combination cytotoxic regimens [85,89-92].

Inflammation of actinic keratoses — There are isolated reports of patients receiving systemic chemotherapy, particularly cytotoxic chemotherapies, who developed erythematous papules and plaques in photodamaged areas that, on closer inspection, were actually inflamed actinic keratoses [93-96].

RADIATION RECALL DERMATITIS AND RADIATION ENHANCEMENT

●Radiation recall dermatitis – Radiation recall dermatitis (RRD) is an uncommon, inflammatory skin reaction that develops in an area of previously irradiated skin after administration of certain promoting agents [97]. Most cases have been associated with chemotherapy. 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 [98]. (See "Radiation dermatitis", section on 'Radiation recall reaction'.)

RRD was originally described with dactinomycin [99]. Since then, a number of other drugs have also been associated with this phenomenon (table 4), particularly anthracyclines and anthracycline-like drugs [100-104].

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) [103]. However, the occurrence of many of these reactions after the first drug exposure argues against an immune mechanism, and defects in deoxyribonucleic acid (DNA) repair [105] as well as toxic drug effects [103] have also been proposed as causative factors.

Erythema, which may be painful, is the most common sign [106,107]. Vesiculation, desquamation, and ulceration have also been reported [1]. Histologically, epidermal dysplasia; necrotic keratinocytes; and a mixed, inflammatory reaction [108] 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 and may 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 [109,110]. Chemotherapy agents administered by the intravenous 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) [111,112].

Drug interruption or dose reduction are the primary treatments for RRD. Symptomatic treatment includes topical corticosteroids and oral antihistamines. Rechallenge with the same agent does not always lead to symptom recurrence [113].

●Radiation enhancement – Enhancement of the cutaneous 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).

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 [108]. (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 [114,115].

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 [116]. 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 [117].

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".)

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 fluoropyrimidines 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".)

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 5) [118]. The area of enhanced pigmentation may be localized or 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.

Diffuse hyperpigmentation — 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, locally (in sun-exposed areas), or 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 [119-123].

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

●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 instead thought to be secondary to a toxic effect on melanocytes [124,125]. Features that can help to distinguish cutaneous busulfan toxicity from true Addison's disease include normal levels of melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH). (See "Clinical manifestations of adrenal insufficiency in adults".)

●Pegylated liposomal doxorubicin (PLD) can induce a macular hyperpigmentation over the trunk and extremities, including the palms and soles [126]. This reaction has not been described with unencapsulated doxorubicin.

●Hydroxyurea may induce hyperpigmentation of the face, neck, lower arms, palms, and nails; pigmentation can also be accentuated in areas of pressure or trauma [127,128]. This pressure-induced hyperpigmentation is also reported for cisplatin [129].

●Methotrexate can rarely induce a diffuse, brown skin hyperpigmentation [130].

●Procarbazine has been associated with generalized melanosis [131].

Localized hyperpigmentation — Localized 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 the face). However, a suspected local drug reaction may be due to other extrinsic factors that act in combination with the drug. In addition to topical fluorouracil, other drugs that can induce localized hyperpigmentation include thiotepa, ifosfamide, and docetaxel (sites of adhesive placement on the skin); capecitabine, cisplatin, hydroxyurea, and bleomycin (sites of trauma or pressure); and daunorubicin (sun-exposed areas) [1,132]. The 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 localized, 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, the dorsal and plantar surfaces of the feet, the extensor surfaces of the 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), cisplatin [1], and fluorouracil.

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

Patterned hyperpigmentation (serpentine, flagellate, reticular) — 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 [133,134].

Linear (flagellate) hyperpigmentation (picture 4) may be seen with bleomycin [135,136]. 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 [137,138]. Pruritus is often an accompanying symptom.

Hair color changes — 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" [139]. This results from alternating periods of treatment and no treatment.

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

NAIL TOXICITIES

Overview — Nonspecific nail changes are commonly observed during systemic cancer treatment [140]. They include transverse grooves on the nail plate (Beau lines) and onychomadesis (shedding of the nail) due to prolonged inactivation of the nail matrix (picture 5A-B). Fingernails grow approximately 0.1 mm per day. Thus, the distance of a Beau 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 6), and some are described below. After discontinuation of chemotherapy, all of these conditions generally resolve as the nail grows out.

Melanonychia — Medications may induce diffuse hyperpigmentation or banding/streaking of the nail plate (melanonychia striata) or bed. (See "Longitudinal melanonychia".)

Besides fluorouracil, a wide range of agents have been implicated, including alkylating agents, taxanes, antimetabolites (hydroxyurea, cyclophosphamide), anthracyclines, and other antitumor antibiotics such as bleomycin (table 6) [1,140]. 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 6) [141]. Leukonychia is also observed in patients treated with doxorubicin, cyclophosphamide, or vincristine [142].

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 7) [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 [1,143].

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 [144].

A systematic review of 12 studies supports the prophylactic use of frozen gloves and frozen socks for the prevention of taxane-induced nail and skin toxic effects [145]. 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 (14 to -4°F) rather than at the standard temperature of -25 to -30°C (-13 to -22°F) [146].

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].

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 8A-B) are characterized by monomorphic, erythematous papules and are usually defined as "drug rash" in 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".)

The management of patients with a presumptive 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 a therapeutically equivalent 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 2 study, pemetrexed was associated with a papular skin rash in 66 percent of treated patients [147].

Subsequent phase 1, 2, and 3 trials reported a much lower incidence (less than 20 percent) and severity of skin rash, which was attributed to the routine use of dexamethasone 4 mg twice daily for three days starting the day before treatment [148-151]. As a result, premedication with this schedule of dexamethasone has become a standard practice for patients receiving pemetrexed [149]. Whether fewer doses would suffice is unknown.

FIXED DRUG ERUPTION — Fixed drug eruption is 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. The cytotoxic drugs most commonly associated with a fixed drug eruption are listed in the table (table 7).

The characteristic early lesion is a sharply demarcated, erythematous, round to oval macule that develops from 30 minutes to 8 hours after drug exposure and arises in the same location after each exposure (picture 9A-B). One-half occur on the oral or genital mucosa (picture 9D). Within hours, the lesion becomes edematous, forming a plaque, which may evolve to bulla (picture 9C) and eventually to erosion. Lesions persist if the drug is continued, but they resolve within days to weeks after the drug is discontinued, leaving a postinflammatory hyperpigmentation.

Fixed drug eruption is discussed in detail separately. (See "Fixed drug eruption".)

DIFFUSE ERYTHEMA AND EXFOLIATIVE DERMATITIS — Diffuse erythema, which can resemble a morbilliform exanthem, has been described with hydroxyurea, busulfan, and cladribine [152]. 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 (but not intravenous) mitomycin [153-156]. At least some of these cases are thought to be immune mediated.

SEVERE CUTANEOUS DRUG REACTIONS — Many antineoplastic agents may cause life-threatening cutaneous adverse reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) [157].

Whether chemotherapy agents cause erythema multiforme, an immune-mediated reaction in most cases induced 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 [158]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)

Stevens-Johnson syndrome/toxic epidermal necrolysis — 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. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Several anticancer agents have been associated with SJS/TEN (table 8) [157]. Determining the drug causality in patients with cancer 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, patients with cancer may have an increased risk of SJS/TEN due to the malignancy itself [159].

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 10). As the disease progresses, vesicles and bullae form, and within days, the skin begins to slough (picture 11C). 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.

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 putative 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 — 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 [160] and lenalidomide [161].

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 11A-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)".)

Acute generalized exanthematous pustulosis — Acute generalized exanthematous pustulosis (AGEP) is a rare, acute eruption characterized by nonfollicular, sterile pustules on a background of erythema. It is often accompanied by fever and leukocytosis. AGEP can occur within hours and most commonly occurs within two to three days of starting a medication [162]. Although antimicrobials are the most common culprit, a few chemotherapy agents have been implicated, including bleomycin and taxanes [163,164]. Medications given as premedications for chemotherapy, such as histamine 2 (H2) blockers and acetaminophen, have also been linked with AGEP [165,166]. (See "Acute generalized exanthematous pustulosis (AGEP)".)

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS AND SCLERODERMA-LIKE CHANGES — Subacute cutaneous lupus erythematosus, which presents with annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 12A-B), has been reported following taxanes [167-169], fluoropyrimidines [170], doxorubicin plus cyclophosphamide [171], and gemcitabine [172]. While phototoxicity may play a role in initiating or sustaining active subacute cutaneous lupus erythematosus, the pathogenesis also involves autoimmunity. This is supported by the presence of deposits of immunoglobulin G (IgG) and complement components at the dermal-epidermal junction, immunohistopathologic findings that are identical to those found in idiopathic disease. Another shared feature of drug-induced and idiopathic subacute cutaneous lupus erythematosus is the presence of circulating 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 [173], gemcitabine [174], and docetaxel [175,176]. Data from the World Health Organization (WHO) pharmacovigilance database (VigiBase) found that anticancer drugs were the most represented drug class responsible for the reported cases of drug-induced systemic sclerosis [177]. These included taxane-based agents, bleomycin, vinblastine, dacarbazine, and pemetrexed. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

MISCELLANEOUS REACTIONS

●Leg ulcers – Treatment-induced leg ulcers occasionally occur in patients taking long-term hydroxyurea for myeloproliferative disorders [178-181]. 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 [181].

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".)

●Pseudocellulitis – Pseudocellulitis has been first and most commonly reported following administration of gemcitabine [182] but has also been described with pemetrexed [183]. Typically occurring within two to three days of chemotherapy administration, patients present with bright red erythema and pain but usually in a bilateral distribution. The pathogenesis is hypothesized to occur via accumulation of chemotherapy within the interstitial space of edematous extremities, resulting in a toxic effect. The resolution time depends on the causative drug's pharmacokinetics and may persist until the drug is displaced from the tissue [184]. Symptomatic management consists of topical steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and antihistamines.

●Grover's disease – Grover's disease, or transient acantholytic dermatosis, has been reported with cytotoxic chemotherapy administration [185]. Clinically and histologically, the findings are indistinguishable from nonchemotherapy-associated presentations, though patients may be less symptomatic. Treatment is with topical steroids, with lotions or creams preferred over ointments given their less occlusive quality.

●Other reactions – There are many other rare cutaneous reactions that have been attributed to chemotherapy agents, including Sjögren syndrome, dermatomyositis, Raynaud 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 9).

SUMMARY

●Toxic erythema of chemotherapy – Toxic erythema of chemotherapy (TEC) is an umbrella term encompassing various cytotoxic reactions that can occur with chemotherapy. It occurs most frequently in patients treated with doxorubicin, pegylated liposomal doxorubicin (PLD), fluoropyrimidines (fluorouracil, capecitabine), cytarabine, and docetaxel but may occur with many other drugs (table 1). The most frequently seen clinical presentation involves the hands and feet (hand-foot syndrome [HFS], also called palmar-plantar erythrodysesthesia). Affected patients initially complain of a tingling sensation, which is followed by edema and tender, symmetric erythema most pronounced over the fat pads of the distal phalanges (picture 1A-B). HFS is dose related and usually resolves within two to four weeks after discontinuation of the causative agent. (See 'Toxic erythema of chemotherapy' above.)

●Neutrophilic eccrine hidradenitis – Neutrophilic eccrine hidradenitis (NEH) presents with erythematous, edematous plaques (picture 2A-B) in patients with malignancy (with or without chemotherapy), with infections, or receiving a variety of chemotherapeutic agents (table 3). (See 'Neutrophilic eccrine hidradenitis' above and "Neutrophilic dermatoses", section on 'Palmoplantar eccrine hidradenitis'.)

●Photosensitivity reactions – Phototoxic and photoallergic reactions have been associated with a variety of chemotherapy agents, of which the most common is methotrexate. A phototoxic reaction is a nonimmunologically mediated reaction that resembles an exaggerated sunburn, with erythema, edema, pain, and tenderness in sun-exposed areas (picture 3A-B). Photoallergic reactions are a delayed hypersensitivity reaction characterized by a pruritic, papulovesicular eruption that involves sun-exposed areas but may spread to non-sun-exposed areas. Photorecall and photoenhancement reactions have been reported with methotrexate and taxanes. (See 'Photosensitivity reactions' above.)

●Radiation recall dermatitis and radiation enhancement – 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 and radiation enhancement' above.)

●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 5). The hyperpigmentation can be localized or diffuse, sometimes with distinctive patterns, such as serpentine or flagellate (picture 4). Hair color changes can occur with cisplatin, cyclophosphamide, and methotrexate. (See 'Pigmentary changes' above.)

●Nail toxicities – Nail changes, such as hyperpigmentation and onycholysis (picture 7), 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 6). (See 'Nail toxicities' above.)

●Exanthematous eruptions and fixed drug eruptions – Exanthematous (maculopapular) eruptions, including morbilliform rashes (picture 8A-B), and fixed drug eruptions (picture 9A-D) may occur in association with many chemotherapeutic agents (table 7). (See 'Exanthematous (maculopapular) eruptions' above and 'Fixed drug eruption' above and "Exanthematous (maculopapular) drug eruption" and "Fixed drug eruption".)

●Severe cutaneous drug eruptions – A number of antineoplastic agents (table 8) may cause severe cutaneous reactions, such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) (picture 11A-D). SJS/TEN is a rare, life-threatening cutaneous reaction characterized by extensive necrosis and detachment of the epidermis due to massive keratinocyte apoptosis (picture 11C). 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 and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Subacute cutaneous lupus erythematosus and scleroderma – Subacute cutaneous lupus erythematosus, manifested by annular or polycyclic, photodistributed, erythematous, and scaling lesions (picture 12A-B), has been reported in a few cases following docetaxel, fluorouracil, or capecitabine. Scleroderma-like changes, consisting of edema, tightening, and induration of the skin on the trunk and extremities, have been reported in patients treated with taxane-based agents, bleomycin, vinblastine, dacarbazine, and pemetrexed. (See 'Subacute cutaneous lupus erythematosus and scleroderma-like changes' above.)

●Uncommon reactions – Uncommon reactions, including leg ulcers, pseudocellulitis, 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 9). (See 'Miscellaneous reactions' above.)