Chemotherapy-Induced Alopecia

Etiology and Biocharacteristics

The hair follicle is a highly organized structure within the skin. At the base of every follicle is a collection of rapidly dividing matrix cells that form an outwardly growing hair shaft. Hair follicle formation is complete at birth, with approximately 100,000 terminal hair follicles on the infant scalp.² Although pharmacologic intervention has been helpful to aid in hair regrowth, hair follicles cannot be regenerated if they are destroyed.^4–4 The hair follicle cycles through three phases: growth phase (anagen), a short involuting/regressing phase (catagen), and a resting phase (telogen) that results in hair shedding. On the scalp, 85%, 5%, and 10% of the scalp’s hair, respectively, are in these phases at a given time.⁵ Stem cells from the hair bulge, a permanent portion of the follicle, act as an endless source of hair matrix cells. The hair matrix cells subsequently divide during the proliferative anagen phase, marking the beginning of the hair cycle.

In general, the most common mechanism for cytotoxic chemotherapy-induced alopecia (CIA) is anagen effluvium—that is, a pattern of hair loss in which anagen hairs are selectively shed.6,7 Because cytotoxic agents target rapidly proliferating cell populations, they attack not only cancer cells but also the rapidly dividing hair matrix cells in anagen phase. This toxic effect on the follicle, as well as the hair shaft itself, leads to anagen hairs falling out with mild pressure, or breaking off at the scalp surface as a result of increased hair fragility (due to weak points in the hair shaft, referred to as Pohl-Pinkus constrictions).⁶ Molecularly, the mechanism by which these changes occur is largely unknown. However, the nuclear transcription factor p53 is thought to play a crucial role in initiating apoptosis in anagen effluvium-type CIA,² because CIA does not develop in mice lacking p53 when they are treated with cyclophosphamide.^8,9 Fas and c-kit have also been implicated.¹⁰ The duration of time until recovery, hair regrowth, and hair repigmentation appears to be dependent on the therapeutic dose and the degree of follicular dystrophy.^8,9 Because the permanent pool of stem cells in the follicle is unaffected by most chemotherapy agents, CIA is typically reversible.¹¹

Another mechanism for cytotoxic CIA is telogen effluvium, a type of hair loss that occurs when a greater proportion of anagen hairs transition into the catagen/telogen phase simultaneously. Hair shedding 3 to 4 months after the initial drug exposure is characteristic of persons with telogen effluvium because the duration of the catagen/telogen hair phases last approximately 3 to 4 months. Agents that frequently lead to telogen effluvium include methotrexate, 5-fluorouracil, and retinoids.⁶ The remainder of this section will discuss anagen effluvium-type CIA.

Epidemiology

The incidence of CIA is unclear given the lack of standardized grading scales or large epidemiological studies.¹ However, certain drugs are more commonly associated with CIA, including cyclophosphamide (an alkylating agent), bleomycin and dactinomycin (antitumor antibiotics), doxorubicin (an anthracycline), irinotecan and topotecan (topoisomerase inhibitors), and docetaxel and paclitaxel (taxanes).^4,12,13 In addition to the cytotoxic agent, the risk of CIA also depends on the drug route, dose, and frequency of administration.¹² For example, high-dose, intermittent, intravenous, and combination chemotherapy regimens are more likely to induce alopecia than are low-dose single agents.^4,14,15

Clinical Manifestations

Anagen effluvium-type CIA mainly affects the scalp, given the large percentage (85%) of anagen hairs at this site. Other sites including the eyebrows, eyelashes, beard, genitalia, and axillae can also be affected over time, although much less frequently.2,16 Anagen effluvium typically begins within days to weeks after initial drug exposure and worsens during the next 1 to 2 months.¹⁷ Patients may initially describe hairs on their pillowcase in the morning or collecting in their shower. Reduced scalp hairs are noticeable once 24% to 40% of a person’s hair is lost¹⁷ and can manifest with diffuse, patchy, or complete hair loss.¹² Although the vertex (top) of the scalp is the most common site for hair loss, Yun and Kim⁷ recently demonstrated that the presence or absence of frontal hairline hair loss (described as a “receding” hairline) appears to differ based on gender. Women are less likely to lose hair at their frontal hairline compared with men, mimicking the gender-based differences seen in androgenetic or male-pattern baldness. In addition, alopecia was found to be asymptomatic in 50% of patients, with the remainder reporting associated pain (15.6%), pruritus (12%), or both (11%).⁷

Multiple studies, particularly in women undergoing treatment for breast cancer, have demonstrated that CIA dramatically reduces patients’ quality of life (QoL). In a literature review of patients with breast cancer, alopecia was consistently thought of as the most devastating chemotherapy-related adverse effect, resulting in decreased QoL and poor self-image.¹⁸ Yeager and Olsen⁶ summarized the following information: Study patients have reported that losing their hair was a worse experience than losing their breast, that the hair loss was a visible reminder of their cancer to others as well as to themselves, and that the severity of the psychological effect was not related to hair loss severity.⁶ In fact, some women have refused chemotherapy because of the risk of losing their hair, and in one study, 8% of women considered refusing chemotherapy because of the risk of CIA.¹⁸ Although most QoL studies have focused on women receiving chemotherapy for breast cancer, recent studies suggest that men often have similar and equally negative experiences with CIA as women, ranking alopecia as one of the most severe and bothersome chemotherapy adverse effects.⁶ In fact, an equal number of male patients were found to be receptive to paying increased fees in order to receive a chemotherapy regimen that would reduce their risk of experiencing CIA.¹⁹

Workup

No laboratory workup is necessary because CIA is diagnosed clinically. Quantifying the severity of alopecia is recommended. The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) has proposed a grading scale (Table 44-2), and other scales exist as well.^1,6

Table 44-2

Chemotherapy-Induced Alopecia Grading Scale* and Proposed Treatment Algorithm

Grade/Severity	Description	Treatment
0		Prevention:  Counseling – Discuss anticipated alopecia – Evaluate anticipated reaction and consider preemptive psychological evaluation – Provide list of resources for camouflage preemptively  Not routinely recommended: Scalp cooling, AS100, scalp tourniquet

1 = MILD TO MODERATE

 Hair loss <50% of normal

 Not obvious from a distance (only on close inspection)

 A different hairstyle may be needed to cover hair loss

 Does not require a wig or hairpiece

Preemptive Counseling

It is important for the clinician to fully appreciate the extremely negative and often devastating psychological impact that both male and female patients who undergo chemotherapy can experience with rapid loss of hair. Prior to initiation of chemotherapy, patients should be counseled that CIA will be a likely adverse effect. Physicians should evaluate patients’ perception of CIA and develop a plan for coping with the anticipated adverse effect. A multidisciplinary approach that includes psychiatric services may be necessary. A list of local hair resources such as scarf stores, fitted wigs, and head coverings should be provided. A prescription for a fitted hair prosthesis can be provided; such a prosthesis may or may not be reimbursed by the patient’s health insurance. Internet sites and alopecia support groups, such as the American Cancer Society or the National Alopecia Areata Foundation, can also provide local resources for patients and families.² Treatment agents to prevent CIA and to promote hair regrowth have been studied. A treatment algorithm based on randomized controlled trial (RCT) data is presented in Table 44-2.

Preventive Treatment

Scalp cooling via the use of ice packs or cooling cap devices is by far the most well-studied and well-published technique for preventing CIA, dating back to the 1970s. Scalp hypothermia is postulated to prevent CIA by reducing blood perfusion and therefore chemotherapy delivery to the scalp, reducing intrafollicular metabolism.⁶ Despite differences in chemotherapy regimens, patient populations, hair-loss evaluation methods, and cooling mechanisms, a significant advantage in the amount of hair preserved with scalp cooling during chemotherapy was found in six of seven RCTs.^2,6 Although cooling cap devices are broadly used in Europe, they were banned in 1990 by the U.S. Food and Drug Administration (FDA) because of safety concerns and lack of reproducible results. Given the concern that cooling could provide a protective environment for micrometastases, the use of scalp cooling caps are not recommended for patients with hematologic malignancies (e.g., mycosis fungoides or acute myeloblastic leukemia), and frequent scalp evaluations are recommended if cooling devices are used.^2,6

Beside scalp cooling, other treatments that have been shown to be effective in preventing CIA include scalp tourniquets (in which a sphygmomanometer cuff headband is used to decrease the blood supply to the head) and the use of AS101, a carboplatin-related immunomodulating drug. In a phase 2 RCT of 58 patients, AS101 was found to significantly decrease the incidence and severity of CIA in patients treated with carboplatin/etoposide therapy compared with control subjects.5,21 Its protective effect against CIA is unclear but is thought to be linked to an upregulation of macrophage-derived factors, including interleukin-1.²¹ In contrast, topical minoxidil 2% and topical calcitriol (a vitamin D3 analog) were found to lack efficacy in preventing CIA.^6,22–24

Treatments for Acceleration of Hair Growth After Chemotherapy

Once CIA is noted by the physician, the hair loss should be acknowledged. Treatment intervention may include camouflage¹⁶ or agents aimed at accelerating hair regrowth. Three modulators of the hair growth cycle (minoxidil, cyclosporine A, and 17-β-estradiol) have shown promise in animal studies. However, only topical minoxidil has been evaluated in a human RCT. Although topical minoxidil 2% has been shown to be ineffective in preventing the onset of CIA, a topical minoxidil 2% solution applied twice daily was found to shorten the period from hair loss to regrowth from 137 days to 50 days.⁶

Epidemiology

The true incidence of chemotherapy extravasations is unknown. The incidence of intravenous, vesicant chemotherapy extravasation is estimated to be 1% to 6%.1,29,30 The concentration, type, and amount of vesicant, as well as the location of extravasation, can all influence the degree of resultant tissue necrosis.²⁹ Additional risk factors include highly alkaline, acidic, or hypertonic solutions; rigid or indwelling vascular access devices; and patient characteristics, including sclerosed or fragile veins, obesity, an inability to verbalize pain, or an impaired sensory perception.^29,30

Clinical Manifestations

After accidental drug extravasation of chemotherapy agents into the surrounding tissue, a wide range of symptoms and manifestations occur. Clinical manifestations can be subdivided into vesicant or irritant extravasation reactions (Figs. 44-1 and 44-2). The clinical manifestation of vesicant drug extravasation can range from local swelling, erythema, burning, or pain to blistering, induration, and progression to skin necrosis. This presentation can also be complicated by deep tissue infection. Symptoms of unintentional extravasation can present immediately after the administration of an agent or therapeutic intervention, or they can develop days to weeks later.²⁸ In contrast, irritant drug extravasation presents with milder symptoms associated with inflammation, including pain, warmth, edema, and erythema. Although irritating, these symptoms typically resolve within weeks and do not have long-term sequelae or necrosis.²⁸

Workup

Extravasation injury should be suspected in any patient with persistent pain, erythema, and swelling, even in the absence of ulceration, and immediate action should be taken. Serial neurovascular examinations and compartment examinations are appropriate to monitor for impending compartment syndrome.²⁸ If the injury is severe or complicated by neurovascular changes, surgical consultation is required.

Treatment

Data regarding the treatment of extravasation injuries is largely limited to case reports and case series. However, several treatment guidelines have been published.29,31–34

Prevention

Prevention is the cornerstone of management of chemotherapy extravasation reactions. Anecdotal guidelines published in the literature are presented in Box 44-1.⁴⁵

Box 44-1

Recommendations for Prevention of Extravasation Necrosis

• Prevention begins with selection of the infusion site.

• The preferred site of infusion is the proximal forearm that has not been surgically compromised, and where a large amount of subcutaneous tissue overlies vital structures.

• Dorsal surfaces of the hands and the antecubital fossae, as well as extremities that have been sites of extensive ablative surgery, should be avoided. If these tissue-poor areas must be used, a subcutaneous flexible indwelling catheter is preferred rather than the standard intravenous needle. When multiple infusions are anticipated over a prolonged period, placement of subcutaneous reservoirs with long indwelling lines should be considered. Drugs should always be administered through a free-flowing intravenous line. Any hint of obstruction within the line calls for immediate termination of the infusion and an attempt at correcting the problem.

• Every attempt should be made to administer a solution that is as dilute as possible over the shortest period of time to prevent injury from concentrated drug and eliminate lengthy exposure of tissues to a toxic agent.

Data from Hannon MG, Lee SK. Extravasation injuries. J Hand Surg 2011;36(12):2060–5 and Wengstrom Y, Margulies A. European Oncology Nursing Society extravasation guidelines. Eur J Oncol Nurs 2008;12(4):357–61.

Pharmacologic and Surgical Treatment

Prompt recognition and treatment of extravasation reactions is necessary, because delayed management can lead to unnecessary tissue necrosis, scarring, and contracture.²⁸ After recognition of extravasation injury, several steps should be taken. These recommendations are presented in Table 44-4.⁴⁵ Notably, dexrazoxane, 500 mg, is the first agent approved by the FDA for treatment of chemotherapy extravasation injuries, specifically those associated with anthracyclines. In clinical trials,^32,39,40 this medication was shown to definitively decrease the need for surgical intervention.

Table 44-4

Drug-Specific Treatments for Extravasation Necrosis

General Recommendations	Source
Stop infusion immediately	Prospective observational study35
Leave intravenous cannula in place and attempt to remove as much of the vesicant as possible with a 10-mL syringe	Retrospective review36
Saline flush-out technique – Goal: to remove as much vesicant as possible (total of 500 mL fluid recommended)

Retrospective review³⁶
Consensus guidelines²⁹ VINCA ALKALOID AND TAXANE EXTRAVASATION GOAL: DISPERSION AND DILUTION OF AGENT Local heat application to disperse the drug (20 minutes, 4 times daily × 1-2 days) Consensus guidelines²⁹ Hyaluronidase local subcutaneous injection (150-1500 IU diluted in 1 mL of sterile water) Anecdotal²⁹ ANTHRACYCLINE EXTRAVASATION GOAL: PREVENT DISPERSION AND NEUTRALIZE AGENT Cold compresses to prevent dispersion

– 20 min, 4 times daily for 1-2 days

Consensus guidelines^29,31,37,38 Dexrazoxane administration (approved by the U.S. Food and Drug Administration)

Clinical trials^32,39–41 Topical dimethylsulfoxide 99% application (use is controversial)

Consensus guidelines^29,37
Prospective study^38,42,43 MECHLORETHAMINE (NITROGEN MUSTARD) EXTRAVASATION GOAL: PREVENT ALKYLATION AND TISSUE DESTRUCTION BY PROVIDING SUBSTITUTE SUBSTRATE FOR ALKYLATION IN THE TISSUE Sodium thiosulfate (use is controversial)

Consensus guidelines^29,33,44

Epidemiology

Although it is believed to be fairly common, the rate of pigment alteration in patients treated with cytotoxic chemotherapy agents is unknown. The incidence of hyperpigmentation varies by agent, with certain medications being more commonly associated with pigmentary alterations than others. For example, hyperpigmentation develops in up to 20% of patients treated with bleomycin and in up to 5% of patients treated with 5-fluorouracil (5-FU).⁵³ In addition, chemotherapy-related hyperpigmentation has not been found to correlate with any systemic effects of chemotherapy, with no health threats other than concerns for cosmesis.^54,55

Clinical Manifestations

Please see Figure 44-3 and refer to Table 44-5 for specific hyperpigmentation changes related to chemotherapeutic agents.

BCNU (carmustine) Cyclophosphamide Mechlorethamine Thiotepa ANTIBIOTICS   Actinomycin Bleomycin Dactinomycin Daunorubicin Doxorubicin MITOTIC INHIBITORS Etoposide Ifosfamide Mithramycin Paclitaxel Procarbazine ANTIMETABOLITES 5-Fluorouracil Methotrexate MISCELLANEOUS DRUGS Cisplatin Hydroxyurea

Generalized Hyperpigmentation

Addison disease or primary adrenal insufficiency, which could be caused by metastatic carcinomas or Hodgkin lymphoma, causes a diffuse hyperpigmentation, often exacerbated by exposure to the sun, with constitutional symptoms of fatigue, anorexia, and malaise. In contrast to busulfan, Addison disease also involves the oral mucosa and is accentuated in skin folds, skin creases, areolae, and genitalia. In contrast to chemotherapy-induced hyperpigmentation, ACTH levels are elevated in persons with Addison disease, with an abnormal response to ACTH stimulation.

Hemochromatosis, an iron storage disease, shows diffuse bronze pigmentation. The acquired form can present in patients who have received multiple blood transfusions. Hepatomegaly is usually present. Hyperpigmentation is due primarily to melanin, but hemosiderin deposition can also be present in the skin.

Advanced metastatic melanoma can be associated with generalized hyperpigmentation and melanuria.

Localized Hyperpigmentation

Melasma is an acquired macular brown pigmentation of the face that becomes pronounced with sun exposure. It can be seen during pregnancy and in patients who take an oral contraceptive or undergo phenytoin therapy. Multiple pigmented longitudinal nail bands can occur as a normal finding among dark-skinned individuals and can be seen in persons with metastatic melanoma. These bands are caused by benign melanocytic hyperplasia, lentigines, or junctional nevi within the nail matrix.

Diffuse brown nail pigmentation can be caused by drugs other than cytotoxic agents, such as antimalarial agents, phenothiazines, tetracyclines, psoralens, and heavy metal therapy. These agents share a similar mechanism with chemotherapy agents.

Increased melanin deposition in tissues can be caused by drugs such as tetracyclines and antimalarial agents. Although this pigment deposition characteristically occurs on the shins and face, any area on the body can be affected.

Hand-Foot Syndrome

Etiology and Biocharacteristics

HFS is a common, painful, erythematous eruption of the palms and soles associated with cytotoxic chemotherapy agents. In the current literature, this syndrome is referred to as either HFS or palmar-plantar erythrodysesthesia. During the 1980s, HFS was referred to as chemotherapy-induced acral erythema. However, this nonspecific descriptive nomenclature has largely been abandoned.⁵⁸ Of note, HFS associated with cytotoxic drugs should not be mistaken for hand-foot skin reaction (HFSR), a condition associated with newer, molecularly targeted agents that is described later in this chapter.

Multiple cytotoxic drugs have been reported to cause HFS. Most commonly, these drugs include pyrimidine analogs (e.g., capecitabine, cytarabine, and 5-FU), anthracyclines (pegylated liposomal doxorubicin more than doxorubicin), and taxanes (e.g., docetaxel).⁵⁹ Less commonly reported causative agents include paclitaxel, hydroxyurea, methotrexate, 6-mercaptopurine, cyclophosphamide, cisplatin, daunorubicin, etoposide, vinorelbine, irinotecan, epirubicin, 6-thioguanine, and tegafur.⁵⁸

Although the pathogenesis of HFS is unknown, a direct toxic effect of chemotherapeutic agents on the skin is considered the most likely mechanism.⁶⁰ Factors hypothesized to play a role include the more rapid cell division in palmoplantar skin compared with back skin,⁶¹ an increased concentration of capecitabine’s activating enzyme (thymidine phosphorylase) in palmoplantar locations,^61,62 an overexpression of cyclooxygenase 2 in the skin as a result of chemotherapy resulting in inflammation,⁶³ and increased drug concentration in the eccrine glands of the palms and soles as a result of drug excretion in sweat.^66–66

A role for excretion from sweat glands is supported by the observation that taxanes and liposome-encapsulated doxorubicin can affect areas besides the hands and feet that have an abundance of sweat glands, such as inguinal areas and the axillae. Recent investigations using laser scanning microscopy have shown that liposomal doxorubicin reaches the skin surface via sweat glands and is deposited in the stratum corneum.65,67 However, it is unclear to what degree different cytotoxic drugs share a similar mechanism in causing HFS, and further research is necessary.

Epidemiology

The overall incidence rates for HFS have been reported to vary between 5% and 89%, based on the cytotoxic agent, drug formulation, and administration schedules.59,68 In persons with this condition, symptoms were dose limiting in 30% of patients.⁶⁹

Risk factors for the development of HFS appear to be related to factors that prolong drug exposure to the cytotoxic agent, including higher doses, greater cumulative doses, drug formulations that increase a drug’s half-life (e.g., liposomal encapsulation of doxorubicin), and increased frequency of administration (e.g., oral daily ingestion of capecitabine, continuous intravenous 5-FU infusions, or a greater number of treatment cycles).⁵⁸ Although unconfirmed, patient-specific risk factors have been reported to include the occurrence of mucositis, neutropenia, and peripheral neuropathy.⁷⁰

Clinical Manifestations

The onset of symptoms is typically within 2 to 3 weeks of drug initiation⁵⁷ but may range from within a few days to up to 10 months as a result of cumulative exposure.⁷¹ Patients initially report a prodrome of tingling sensation or pain in the palms and/or soles. Typically, within a few days, patients progress to the development of painful, symmetric, well-demarcated erythema and edema of palmoplantar skin. The eruption is initially most pronounced over the fat pads of the distal digits, lateral fingers, and the thenar and hypothenar eminences of the palms, but typically generalizes to a diffuse erythema (Fig. 44-4). Skip areas may occur, as can extension to the dorsal surfaces of the extremities. HFS may also rarely involve the penis and scrotum,⁷² axillae groin, waist, inner side of knees, posterior side of elbows, anterior folding lines of wrists, sacral area, and bra line.⁷¹

Clinical symptoms can vary by severity, ranging from mild, nontender fine peeling to severe, extremely painful bullous disease with functional impairment. A particularly severe bullous variant that progresses to full-thickness epidermal necrosis and sloughing can occur.⁶⁸ Nagore et al.⁶⁸ described the natural history of HFS. The toxicity tends to worsen with continued therapy, with increasing restriction of fine movements of the digits as a result of swelling and pain. The erythema becomes darker or violaceous and diffusely covers the palms and soles. Swelling and severe pain at rest may ultimately occur, with daily activities being limited.

For persons with HFS, clinical manifestations affecting a patient’s daily functional activities may necessitate dose modification.⁷³ The development of the HFS-14, a QoL scale designed specifically to evaluate the impact of HFS, is a promising development that will help standardize research trials.⁷⁴

Workup

A skin biopsy is not typically indicated because the histologic changes of this toxicity are nonspecific. Treatment of HFS should be guided by severity; however, severity-guided treatment algorithms are lacking the literature. Because HFS is a painful condition and may limit daily activities, functional impairment is a component of the grading system to determine the severity of HFS (Table 44-6).

Table 44-6

Classification/Grading of Hand-Foot Syndrome Severity*

Grade/ Severity	Clinical Manifestations
0
1 = mild	Minimal skin changes (mild erythema, edema, or desquamation)  No pain  No interference with normal activities

2 = moderate

 Moderate skin changes (peeling, blisters, bleeding, edema, or hyperkeratosis)

 With pain

 Limiting instrumental ADLs, but not precluding normal activities

 Moderate; minimal, local or noninvasive intervention indicated

Hand-Foot Skin Reaction

HFSR is a cutaneous toxicity affecting the palms and soles that is associated with molecularly targeted agents, including multikinase inhibitors (MKIs) and BRAF inhibitors (BRAFIs). HFSR differs from HFS in many ways. In contrast to HFSR, HFS affects hands more severely than feet and can affect nonpalmoplantar skin as well; in addition, the eruption is typically more confluent (Table 44-7).^60,75

Dose Reductions

Dose modification regimens are based on the individual drug per manufacturers’ and/or phase 3 RCT guidelines. In some patients, a moderate reduction in chemotherapy dosage and intensive topical care allows continuation of infusion therapy.⁸⁴

Prevention

In general, wound care to prevent infection, elevation to reduce edema, and symptomatic treatment of pain are recommended.⁶⁸ Routine application of topical emollients (e.g., lanolin/petrolatum-based ointments or udder cream) is also recommended.⁷⁷

Four phase 3 RCTs have been performed to evaluate preventative treatment agents. Only one RCT, which evaluated the efficacy of celecoxib, 200 mg twice daily, demonstrated prophylactic efficacy in persons with HFS, reducing the incidence of HFS from 74.6% in control subjects to 57.4% with the addition of celecoxib.⁷⁶ In contrast, two RCTs demonstrated no efficacy of pyridoxine, 200 mg/day, in patients treated with pegylated liposomal doxorubicin or capecitabine compared with control subjects.^79,80 However, a three-arm retrospective study evaluating prophylactic versus symptomatic pyridoxine compared with control subjects demonstrated that patients who took >200 mg of pyridoxine a day had better symptom control of their HFS than did patients who took a smaller dose.⁸¹ These findings suggest that the dose of pyridoxine in the RCTs was insufficient to obtain an effect. Finally, an RCT evaluating the prophylactic efficacy of twice-daily urea-lactic acid cream in patients treated with capecitabine was found to be ineffective as well, suggesting that emollients without these exfoliative properties may be preferable.⁷⁸

Preventative treatments suggested to be helpful, but that have not been confirmed, include the routine use of topical moisturizers, regional cooling during infusions, nicotine patches, oral vitamin E, and systemic steroids (Table 44-8).

Reactive/Symptomatic Treatment

Other therapies that have been used with some reported benefit of symptom alleviation include oral corticosteroids, vitamin E, celecoxib, pyridoxine, and topical 99% dimethylsulfoxide (Table 44-8).

Epidemiology

The incidence of chemotherapy-induced NEH is unclear. The chemotherapy drugs that are most frequently reported to cause NEH are cytarabine and daunorubicin. Other chemotherapeutic agents reported include doxorubicin, vincristine, dacarbazine, bleomycin, cis-platinum, methotrexate, 6-thioguanine, dactinomycin, cyclophosphamide, mitoxantrone, daunoblastina, chlorambucil, 5-FU, VP-16, etoposide, and idarubicin.97,102,103

Clinical Manifestations

Lesions may appear within 2 to 3 days of starting chemotherapy or may go unnoticed until weeks after chemotherapy has started. Classically the eruption begins within 2 to 3 weeks of the initiation of therapy. Affected patients present with a wide variety of cutaneous lesions, and hence the clinical picture is nonspecific (Fig. 44-5). Tender erythematous to purpuric macules, papules, nodules, or plaques can appear on any area during active administration of a cytotoxic agent. Lesions may or may not have central necrosis. The eruption most commonly affects the trunk and extremities but may involve the palms, soles, and even the face. Some unusual presentations include periorbital edema with erythema and injection site reactions. Usual manifestations include hyperpigmented plaques and painful edema of the ears. Fevers may accompany the onset of cutaneous lesions.¹⁰⁴

Workup

NEH is a histologic diagnosis in which neutrophilic infiltration of the eccrine gland is noted. A skin biopsy demonstrating typical pathological changes of the eccrine glands is required to confirm a diagnosis of NEH.

Differential Diagnosis

Clinical

The differential diagnosis includes leukemia cutis, cutaneous tumor metastases, erythema multiforme, vasculitis, drug hypersensitivity reaction, sepsis (bacterial and fungal), Sweet syndrome, and pyoderma gangrenosum. The localized nature of lesions associated with NEH and the temporal relationship of cutaneous lesions to the administration of chemotherapy should aid clinically in differentiating chemotherapy-induced NEH from most diseases.

Histological

ESS is essentially a noninflammatory version of NEH and is diagnosed exclusively by histology. It has been suggested that the lack of neutrophils is a result of chemotherapy-induced neutropenia rather than reflective of it being a distinct entity.¹⁰⁵

Treatment

Although some studies support the use of systemic corticosteroids to treat NEH, the course or the disease does not appear to be influenced by chemotherapy protocols that often include high dosages of systemic corticosteroids. There are a few case reports of recurrent lesions that have been suppressed with concurrent dapsone administration.106,107

Prognosis

NEH is a benign, self-limiting disease that generally requires no treatment. After discontinuation of the chemotherapy drug, resolution typically begins within 1 week. However, in many patients, skin lesions begin to resolve within 7 to 21 days after onset despite continuous chemotherapy administration. Likewise, new lesions can appear days and weeks after resolution of an original outcropping or might recur with the reinstitution of a course of chemotherapy. New papules, plaques, and nodules also might develop at the sites of initial lesions. Recurrent lesions appear to be less severe than preceding lesions, and healing occurs without residual scarring. The prognosis for total recovery without sequelae is excellent.