Dermatologic Toxicities of Anticancer Therapy
Summary of Key Points
Chemotherapy-Induced Alopecia
• 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.
Hand-Foot Syndrome
• 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.
Radiation Dermatitis
• 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.
Radiation Recall
• 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.
Radiation Enhancement
• 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.
Papulopustular Eruption
• 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.
Hand-Foot Skin Reaction
• 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.
Secondary Squamous Neoplasms
• 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.
1. The most common mechanism responsible for cytotoxic chemotherapy-induced alopecia (CIA) is:
2. True or false: CIA does not typically bother men because it is reversible.
3. Regarding treatment or prevention of CIA, which of the following is true?
A Scalp-cooling measures are ineffective in preventing CIA.
B Scalp-cooling measures should be used with caution given the potential risk for creating a protective environment for micrometastases.
C Topical minoxidil has been shown to both prevent and treat CIA.
D Camouflage with wigs is not considered a mode of treatment.
4. Regarding extravasation injuries, which of the following statements is true?
A Irritant reactions are more severe compared with vesicant reactions.
B Extravasation injury always causes compartment syndrome.
C Reported treatments differ based on the extravasated drug.
5. Hand-foot syndrome (HFS) is synonymous with all of the following, except:
1. Answer: B. A minority of chemotherapy agents can cause a telogen effluvium, such as methotrexate. Although hair fragility may occur with CIA, this is not the main mechanism.
2. Answer: B. Studies have shown that men are adversely affected by CIA.
3. Answer: B. Scalp cooling has been shown to be effective; however, there is concern that this cooling may create a protective environment for micrometastases. Topical minoxidil has been shown to effectively treat CIA but not to prevent it. Camouflage with wigs should be discussed before treatment as one of the most important treatment modalities.
4. Answer: C. Reported treatments differ based on the extravasated drug (see Box 44-1). Vesicant reactions are more severe than irritant reactions, and compartment syndrome is a possible complication, but not a universal one.
5. Answer: C. HFSR is a term for the palmoplantar eruption associated with sorafenib, vemurafenib, and other BRAF-inhibiting agents. Differences are summarized in Table 44-7. HFS has been referred to in the literature as acral erythema, toxic erythema of chemotherapy, and palmar-plantar erythrodysesthesia.
