Dermatologic Toxicities of Anticancer Therapy
Lisa Pappas-Taffer, Kachiu Lee, H. William Higgins, Leslie Robinson-Bostom and Charles J. McDonald
• Etiology: Cytotoxic chemotherapy agents target hair follicles that are in the proliferative growing (anagen) phase, causing an “androgen effluvium.” Less common mechanisms include telogen effluvium.
• Incidence: Chemotherapy-induced alopecia (CIA) is common. The incidence differs based on the agent, dose, and frequency of administration.
• Manifestations: Increased hair shedding and hair fragility occur, with a diffuse or patching alopecia that is noticeable when 25% to 40% of scalp hairs are shed. It may be associated with symptoms of pruritus or pain but is most commonly asymptomatic.
• Complications: CIA can dramatically affect patients’ psychosocial health, resulting in significant reductions in quality of life (QoL).
• Treatment: Most treatment recommendations are based on expert opinion, although a few randomized controlled trials (RCTs) exist. Reported preventive strategies include counseling and the use of scalp cooling, ammonium trichloro(dioxoethylene-O,O-) tellurite (AS101), or scalp tourniquets. For acceleration of hair regrowth, minoxidil, 2% twice daily, has been shown to be effective.
• Prognosis: CIA is typically completely reversible, although up to 60% of patients report changes in the texture, thickness, or color of their new hair.
Cutaneous Extravasation Injury
• Etiology: Extravasation injury is divided into irritant versus vesicant reactions. Irritant agents cause inflammation and erythema, whereas vesicant reactions may cause full thickness skin necrosis.
• Incidence: The incidence of irritant reactions is unknown. The incidence of intravenous vesicant reactions is thought to approach 6%.
• Manifestations: Extravasation of chemotherapeutics can cause a range of unintended adverse effects, including skin inflammation or necrosis. The severity of tissue injury after unintended extravasation ranges from mild erythema to blisters and full-thickness skin necrosis (Figs. 44-1 and 44-2).
• Complications: Pain can be significant, and rarely, compartment syndrome can result.
• Treatment: The offending drug must be stopped immediately. The subsequent treatment differs based on the chemotherapeutic agent used. A treatment algorithm is presented in Box 44-1 and Table 44-4 based on RCTs and expert opinion.
• Prognosis: Mortality is low, but the QoL impact and related morbidity is severe with vesicant chemotherapeutics.
Chemotherapy-Induced Hyperpigmentation
• Etiology: A variety of patterns of cutaneous hyperpigmentation have been described in association with many different cytotoxic agents.
• Incidence: The overall incidence of hyperpigmentation is unknown.
• Manifestations: Cutaneous hyperpigmentation can be generalized or localized and can occur in drug-specific patterns (Table 44-5, Fig. 44-3). Mucous membranes, hair, teeth, and nails can also be affected by changes in pigmentation produced by cancer chemotherapy.
• Complications: Cutaneous hyperpigmentation may be cosmetically displeasing with reduced QoL.
• Treatment: Limited data are available regarding treatment options.
• Prognosis: Skin hyperpigmentation resolves slowly after discontinuation of therapy, and nail pigmentation grows out distally.
• Etiology: Hand-foot syndrome (HFS) has numerous synonyms, including palmar-plantar erythrodysesthesia and acral erythema. It is caused by a variety of cytotoxic chemotherapeutic agents.
• Incidence: The incidence differs based on the cytotoxic agent used, the dose, and the administration frequency. Overall, the incidence ranges from 3% to 89%.
• Manifestations: The clinical manifestations can vary based on severity, ranging from asymptomatic mild erythema or peeling to extremely painful full-thickness epidermal sloughing with significant functional impairment (Fig. 44-4).
• Complications: Reduced QoL due to pain and functional impairment is common. However, rare complications can include prolonged dysesthesias with loss of fingerprints, rare distal necrosis, or secondary infection.
• Treatment: Drug interruption or dose modification is the most well-documented intervention. In general, wound care to prevent infection, elevation to reduce edema, and symptomatic treatment, including routine use of topical emollients, is recommended. Celecoxib has been shown to be effective in preventing HFS in patients receiving capecitabine. Other preventive treatments suggested to be helpful include regional cooling during infusions, nicotine patches, oral vitamin E, and systemic steroids. Therapies reported to be helpful to reduce symptoms include oral steroids, oral vitamin E, celecoxib, and topical 99% dimethylsulfoxide.
• Prognosis: Severe acral pain, inflammation, and possible blister formation can cause considerable morbidity and poor patient compliance. However, it is typically completely reversible after drug discontinuation. Reaction severity is not thought to be related to the patient’s disease status.
Neutrophilic Eccrine Hidradenitis
• Etiology: Neutrophilic eccrine hidradenitis (NEH) is an acute dermatosis that has been associated with multiple chemotherapeutic agents; in addition to malignancies in the absence of chemotherapy, infections (e.g., human immunodeficiency virus), and nonchemotherapeutic drugs. Hence NEH is considered a reactive process. Eccrine squamous syringoplasia (ESS) is a condition that clinically resembles NEH; however, what skin biopsy reveals is a lack of neutrophils.
• Manifestations: Variable (Fig. 44-5).
• Treatment: Dose reduction or interruption.
• Prognosis: The prognosis for both NEH and ESS is favorable.
• Etiology: Radiation dermatitis is caused by ionizing radiation applied to any area of the skin. The severity is dependent on location, body surface area treated, volume of tissues irradiated, total radiation dose received, and the period over which radiation was administered.
• Incidence: Radiation dermatitis occurs in up to 95% of patients receiving ionizing radiation.
• Manifestations: An acute dermatitis typically occurs within 90 days of exposure. Chronic dermatitis usually occurs after 90 days. Clinical manifestations range from mild erythema resembling a sunburn to chronic ulcerations (Fig. 44-6).
• Complications: Chronic nonhealing or infected ulcerations most commonly occur. However, chronic radiation dermatitis may be associated with the development of nonmelanoma skin cancers and angiosarcomas at irradiated sites.
• Treatment: Treatment is symptomatic. Chronic ulcerations may require persistent wound care to prevent infection and optimize skin healing. Hence guidance from wound care specialists may be necessary.
• Prognosis: Prognosis is generally favorable after cessation of radiation therapy.
• Etiology: Radiation recall occurs in a previously irradiated area after administration of a chemotherapeutic agent. The exact mechanism is unclear.
• Incidence: Incidence is unknown, but it is thought to affect up to 12% of all patients receiving chemotherapy medications after radiation therapy.
• Manifestations: Clinical manifestation ranges from mild erythema to severe ulceration and necrosis (Fig. 44-7).
• Complications: Chronic nonhealing or infected ulcerations.
• Treatment: Treatment is symptomatic. Severe or chronic ulcerations should be managed in conjunction with wound care specialists.
• Prognosis: Lesions typically resolve with symptomatic management.
• Etiology: Radiation enhancement occurs when chemotherapeutics act as radiation sensitizers to potentiate the effects of radiation. Chemotherapeutics must be administered within 3 weeks of radiation to produce radiation enhancement.
• Incidence: The incidence rate varies with different agents. No prospective studies have been conducted to examine incidence or prevalence rates of radiation enhancement.
• Manifestations: Clinical manifestations include skin findings that resemble radiation dermatitis and radiation recall.
• Complications: Complications can include full-thickness skin necrosis requiring care that includes treatment by a wound care specialist.
• Treatment: Treatment is symptomatic.
• Prognosis: Lesions typically resolve with symptomatic management.
Atypical Vascular Lesions and Angiosarcomas
• Etiology: Atypical vascular lesions (AVLs) and angiosarcomas are long-term sequelae of ionizing radiation, although the mechanism of tumor development is unclear.
• Incidence: AVLs are thought to be extremely rare, with an unclear incidence rate. Angiosarcomas are estimated to occur in approximately 5 in 10,000 patients.
• Manifestations: AVLs can manifest as multiple, scattered, red papules. Angiosarcomas manifest as ecchymotic-appearing patches.
• Complications: AVLs can regress spontaneously. However, recurrent AVLs may progress to angiosarcomas. Angiosarcomas have a 50% rate of metastasis. Even after treatment, 67% of angiosarcomas may recur.
• Treatment: Tumors tend to have an aggressive course, and surgical excision for both types of tumors is recommended.
• Prognosis: AVLs are typically benign, although they have a potential to transform into angiosarcomas. Prognosis for angiosarcoma is poor, with a 5-year disease-free survival rate of 36% in persons without metastatic disease.
• Etiology: Papulopustular eruption (PPE) occurs with use of epidermal growth factor receptor inhibitors (EGFRIs), cetuximab, panitumumab, erlotinib, and gefitinib; it occurs much less commonly with dual EGFR/HER2 inhibitors (e.g., lapatinib), and it occurs infrequently with multikinase inhibitors (MKIs), (e.g., sunitinib and sorafenib). Although historically referred to as “acneiform,” PPE is clinically and pathologically unrelated to acne.
• Incidence: More than 90% of patients treated with EGFRIs experience PPE.
• Manifestations: PPE is marked by itchy/painful papules and pustules most commonly occurring on the face, upper back, and chest (Fig. 44-8).
• Complications: Secondary cutaneous infections develop in 38% of affected patients. PPE is also often complicated by a reduced QoL.
• Treatment: RCT data are limited. See Table 44-14 for a suggested treatment algorithm based on expert opinion.
• Prognosis: Primarily, the presence and severity of EGFRI-associated PPE often correlate with good tumor response and increased patient survival. Prophylactic treatment, with the goal of reducing rash severity, does not adversely affect the inciting agent’s antitumor effect; instead, it may signal an optimized treatment outcome.
• Etiology: Hand-foot skin reaction (HFSR) is caused by MKIs (e.g., sorafenib and sunitinib), and more recently v600E-BRAF inhibitors (e.g., vemurafenib).
• Incidence: HFSR occurs more frequently in patients treated with sorafenib (33.8%) than with sunitinib (19%), with a significant number of patients having severe grade 3 toxicity (6% to 8%). The incidence of HFSR in patients treated with vemurafenib is 6% to 13%.
• Manifestations: HFSR is marked by painful, erythematous-to-hyperkeratotic plaques with a characteristic halo of erythema that occur focally in areas of friction on palmoplantar surfaces ± bullae (Fig. 44-9).
• Complications: Complications include pain and difficulty performing activities of daily living.
• Treatment: Treatment recommendations are largely anecdotal. See Table 44-15 for a proposed treatment algorithm.
• Etiology: Specific (e.g., vemurafenib) and nonspecific (e.g., sorafenib) BRAF inhibitors.
• Incidence: Secondary squamous neoplasms occur in 18% to 31% of patients receiving vemurafenib and 4% to 6% of patients receiving sorafenib.
• Manifestations: Keratoacantomatous carcinomas (KACs), KAC-type invasive squamous cell carcinoma (KAC-type SCCs), and classic SCCs may appear.
• Prognosis/treatment: There are no reported cases of metastatic disease. Treatment is recommended, although spontaneous involution can be seen. No proposed treatment algorithms are found in the literature.
Cutaneous Complications of Cytotoxic Chemotherapy
Cytotoxic chemotherapy agents are drugs that affect cell division or DNA synthesis and function. The major categories include alkylating agents, antimetabolites, anthracyclines, plant alkaloids, and others. These traditional chemotherapy agents cause many dermatologic adverse effects, including alopecia, stomatitis, hyperpigmentation, nail changes, extravasation reactions, hand-foot syndrome (HFS), and neutrophilic eccrine hidradenitis (NEH). A description of all the cutaneous reactions to cancer chemotherapeutic agents is beyond the scope of this book. Instead, we have elected to highlight a group of reactions that are fairly common and yet unique to cancer chemotherapy. Cutaneous complications can be severe and may modify the ultimate course of chemotherapy, whereas others can be treated symptomatically without adversely affecting the treatment course. See Table 44-1 for a summary of cutaneous toxicities to cytotoxic agents.1
Table 44-1
Cutaneous Toxicities Due To Cytotoxic Chemotherapy
| Agent | Indications |
| ANTIMETABOLITES | |
| Pemetrexed | Exanthem, radiation recall, urticarial vasculitis |
| Capecitabine | Hand-foot syndrome, stomatitis, acral hyperpigmentation, palmoplantar keratoderma, pyogenic granuloma, inflammation of actinic keratoses, mucosal hyperpigmentation |
| Fludarabine | Exanthem, mucositis, hand-foot syndrome, paraneoplastic pemphigus |
| Cladribine | Exanthem, toxic epidermolytic necrolysis |
| Tegafur | Hand-foot syndrome, acral hyperpigmentation, melanonychia, brittle nails, photoallergic and photolichenoid eruptions, pityriasis lichenoides et varioliformis acuta |
| Gemcitabine | Alopecia, mucositis, morbilliform exanthem, radiation recall, linear immunoglobulin A bullous dermatitis, scleroderma-like changes, lipodermatosclerosis, pseudocellulitis (resembling erysipelas), pseudolymphoma, Stevens-Johnson syndrome |
| 5-Fluorouracil | Radiation enhancement, radiation recall, photosensitive reactions, cutaneous and nail hyperpigmentation, hand-foot syndrome, inflammation of actinic keratoses, onycholysis |
| TOPOISOMERASE-INTERACTING AGENTS | |
| Irinotecan | Alopecia, mucositis |
| Topotecan | Alopecia, morbilliform exanthem, neutrophilic eccrine hidradenitis |
| Doxorubicin/liposomal doxorubicin | Hand-foot syndrome, radiation recall and enhancement, neutrophilic eccrine hidradenitis, hyperpigmentation, alopecia, mucositis, ultraviolet recall, extravasation reactions, formation of melanocytic macules |
| Liposomal daunorubicin idarubicin | Alopecia, mucositis, extravasation reactions |
| Radiation recall, alopecia, hand-foot syndrome, mucositis, nail hyperpigmentation, extravasation reactions | |
| ANTIMICROTUBULE AGENTS | |
| Paclitaxel | Alopecia, radiation recall, erythema multiforme, onycholysis, hand-foot syndrome, photosensitivity, scleroderma-like changes, subcutaneous lupus erythematosus, subungual hemorrhage |
| Docetaxel | Mucositis, alopecia, erythema, pruritus, desquamation, hand-foot syndrome, fixed erythrodysesthesia plaque, radiation recall, urticaria, exanthems, nail changes, subungual hemorrhage, scleroderma-like changes, subcutaneous lupus erythematosus, extravasations reactions, photosensitivity |
| Vincristine, vinblastine, vinorelbine | Phlebitis, alopecia, hand-foot syndrome, extravasation reactions |
Modified from Balagula Y, Rosen ST, Lacouture ME. The emergence of supportive oncodermatology: the study of dermatologic adverse events to cancer therapies. J Am Acad Dermatol 2011;65(3):624–35.
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
Camouflage:
Acceleration of hair regrowth:
Infrequent:
Infrequent:
*Common Terminology Criteria for Adverse Events.
Data from Balagula Y, Rosen ST, Lacouture ME. The emergence of supportive oncodermatology: the study of dermatologic adverse events to cancer therapies. J Am Acad Dermatol 2011;65(3):624–35 and Krause K, Foitzik K. Biology of the hair follicle: the basics. Semin Cutan Med Surg 2006;25(1):2–10.
Although many patients are aware of CIA as an adverse effect of chemotherapy, few are prepared for the QoL and psychological impact of this condition. If depression or other mental health issues are suspected, a referral to psychiatry is recommended.20
