Dermatologic Adverse Events During Treatment

Alyx C. Rosen

Yevgeniy Balagula

Shari B. Goldfarb

Mario E. Lacouture

INTRODUCTION

Chemotherapy and radiation have been standard anticancer treatment regimens for decades, and the advent of newer targeted agents has revolutionized the management of patients with various malignancies. However, these anticancer therapies are all associated with a wide range of cutaneous adverse events (AEs) that affect the skin, hair, and nails. The more conventional cytotoxic chemotherapies and radiation cause side effects such as alopecia, stomatitis, and radiation dermatitis, which are well documented. Similarly, the novel targeted therapies have been associated with recently described, specific dermatologic conditions that affect the majority of patients. Regardless of the anticancer therapy involved, these dermatologic AEs can cause significant discomfort to patients and impair their ability to function independently. The inability to care for themselves, along with the physical discomfort, may dramatically diminish patients’ quality of life (QoL). For example, the rash to epidermal growth factor receptor (EGFR) inhibitors can necessitate a dose modification or treatment interruption by 36% and 72% of health care providers, respectively, which may negatively affect the clinical outcome (1). The etiology of each dermatologic AE is highly dependent on the type of anticancer therapy or the specific target molecule in the case of targeted therapies. While the pathomechanism of each dermatologic AE has not been elucidated, much work is being done to understand these processes and identify mechanism-based treatment strategies. This chapter will introduce practitioners to the grading scale, basic pathophysiology, clinical appearance, and management of the most common skin, hair, and nail AEs in oncology.

GRADING OF DERMATOLOGIC ADVERSE EVENTS

An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical device, drug, or procedure that may or may not be considered related to such intervention. As patients frequently experience AEs with anticancer therapies, monitoring for their occurrence is an important part of their medical care. AEs are most commonly measured by the National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Table 25.1), a descriptive classification along with a severity grading scale of side effects from anticancer therapies. The NCI-CTCAE version 4.0 is the current version in use, which was updated from previous versions to reflect improvements in treatment-related AEs and severity descriptions.

EFFECT OF DERMATOLOGIC ADVERSE EVENTS ON PATIENT’S QUALITY OF LIFE

While anticancer therapies can lead to improved progressionfree survival and overall survival rates, the resultant dermatologic AEs can significantly impact patients’ QoL. Certain protocols require that patients receive treatment for extended periods of time making knowledge and treatment of these skin conditions of even greater import. Finally, correlations have linked the severity of cetuximab-induced rash with the extent of tumor response (2). While this has not yet been proven for the other EGFR inhibitors, it emphasizes the importance of proper management of the rash and other skin AEs to minimize patient morbidity and prevent treatment interruption. Various dermatologic QoL scales, including the Skindex-16 questionnaire, have allowed health care professionals treating patients on anticancer therapies to measure how much patients are bothered by their skin conditions. The Skindex-16 is a validated, 16-item, skin-related QoL instrument that is broken down into three domains: symptoms, emotions, and functions. The resultant significant physical and psychosocial discomfort might lead to interruption or dose modification of anticancer agents. Therefore, physicians must be able to recognize and manage cutaneous reactions so that patients can receive these potentially life-prolonging therapies (3).

ADVERSE EVENTS OF THE SKIN—RASH

Papulopustular Rash

Papulopustular rash is the most common dermatologic AE occurring in patients treated with EGFR inhibitors. The incidence varies depending on the specific EGFR inhibitor. The incidences of all-grade rash from single-agent erlotinib and cetuximab previously are reported as 75.2% and 88.2%, respectively (4,5,6). The risk of all-grade rash for vandetanib is 46.1% (7). While the rates of rash are similar for patients treated with erlotinib or cetuximab monotherapy, they are substantially higher than those found in patients treated with single-agent vandetanib.

The etiology of the papulopustular rash is likely a result of inhibition of EGFR, as this has been described for erlotinib, cetuximab, and panitumumab, three EGFR inhibitors (8). EGFR is crucial for the normal physiologic activities of the epidermis, and in the skin, EGFR is predominately localized to undifferentiated, actively proliferating basal and suprabasal keratinocytes (9,10). The formation of the characteristic
EGFR inhibitor papulopustular rash is believed to be the result of direct EGFR inhibition and induction of an inflammatory response secondary to follicular obstruction (11). This leads to increased apoptosis that can typically be detected between days 4 and 12, which is the time of onset of rash in 45% to 100% of patients (12). The rash is characterized by erythematous papules and/or pustules affecting the seborrheic-rich areas, including the face, specifically the cheeks, nose, forehead, chin, perioral regions, and the scalp and upper trunk (13) (Fig. 25.1). Other physical symptoms often associated with the papulopustular rash include pain, pruritus, burning, and irritation in up to 62% of patients, all of which negatively impact a patient’s QoL (14,15).

TABLE 25.1 Common terminology criteria for adverse events version 4.0—selected skin and subcutaneous tissue disorders

AE Term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Alopecia	Hair loss of < 50% of normal for that individual that is not obvious from a distance but only on close inspection; a different hair style may be required to cover the hair loss, but it does not require a wig to camouflage	Hair loss of ≥50% normal for that individual that is readily apparent to others; a wig is necessary to completely camouflage the hair loss; associated with psychosocial impact
Dry skin	Covering < 10% BSA and no associated erythema or pruritus	Covering 10-30% BSA and associated with erythema or pruritus; limit instrumental ADL	Covering > 30% BSA and associated with pruritus; limiting self-care ADL
Hypertrichosis	Increase in length, thickness, or density of hair that the patient is either able to camouflage by periodic shaving or removal of hairs or is not concerned enough about the overgrowth to use any form of hair removal	Increase in length, thickness, or density of hair at least on the usual exposed areas of the body that requires shaving or use of hair removal to camouflage; associated with psychosocial impact
Mucositis	Asymptomatic or mild symptoms; intervention not indicated	Moderate pain; not interfering with oral intake; modified diet indicated	Severe pain; interfering with oral intake	Life-threatening consequences; urgent intervention indicated	Death
Palmar-plantar erythrodysesthesia syndrome	Minimal skin changes or dermatitis (e.g., erythema, edema, and hyperkeratosis) without pain	Skin changes (e.g., peeling, blisters, bleeding, edema, and hyperkeratosis) with pain; limiting instrumental ADL	Severe skin changes with pain; limiting selfcare ADL
Papulopustular rash	Papules and/or pustules covering < 10% BSA, which may or may not be associated with symptoms of pruritus or tenderness	Papules and/or pustules covering 10-30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; associated with psychosocial impact; limiting instrumental ADL	Papules and/or pustules covering > 30% BSA, which may or may not be associated with symptoms of pruritus or tenderness; limiting selfcare ADL; associated with local superinfection with oral antibiotics indicated	Papules and/or pustules covering any % BSA, which may or may not be associated with symptoms of pruritus or tenderness and IV antibiotics indicated; life-threatening consequences	Death
Paronychia	Nail fold edema or erythema; disruption of the cuticle	Localized or oral intervention indicated; edema or erythema with pain; associated discharge or nail plate separation; limiting instrumental ADL	Surgical intervention or IV antibiotics indicated; limiting self-care ADL
Pruritus	Mild or localized; topical intervention indicated	Intense or widespread; intermittent; skin changes from scratching; oral intervention indicated; limiting instrumental ADL	Intense or widespread; constant; limiting selfcare ADL or sleep; oral corticosteroid or immunosuppressive therapy indicated
Radiation dermatitis	Faint erythema or dry desquamation	Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin folds and creases; moderate edema	Moist desquamation in areas other than skin folds and creases; bleeding induced by minor trauma or abrasion	Life-threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site; skin graft indicated
Rash maculopapular	Macules/papules covering < 10% BSA with or without symptoms (e.g., pruritus, burning, and tightness)	Macules/papules covering 10-30% BSA with or without symptoms; limiting instrumental ADL	Macules/papules covering > 30% BSA with or without symptoms; limiting self-care ADL
AE, adverse event; BSA, body surface area; ADL, activities of daily living.

The guidelines for prevention and treatment of papulopustular rash and most dermatologic AEs to anticancer therapies are developed from expert opinion and evidencebased recommendations (Fig. 25.2). Prophylactic topical therapy includes hydrocortisone 1% cream, moisturizers, doxycycline or minocycline, and broad-spectrum sunblock with sun protection factor (SPF) of at least 15 applied twice daily and every 2 hours when outdoors for the first 6 weeks of EGFR inhibitor treatment (16) (Table 25.2). Sun exposure can exacerbate the papulopustular rash and also lead to severe photosensitivity reactions. Minocycline 100 mg and doxycycycline 200mg daily have been shown in randomized trials to reduce the number of lesions during the first 8 weeks of treatment (16,17,18). Dose modification or discontinuation is only recommended for severe skin reaction (grade ≥3). Bacterial and viral cultures should be obtained if infection is suspected, and patients should be treated for the skin reaction with hydrocortisone 2.5% cream, minocycline 100 mg or doxycycline 100 mg twice daily, and prednisone 0.5 mg/kg for 5 days (2,19). Grade 4 skin reactions may require treatment in specialized burn care units.

Figure 25.1. EGFR inhibitor-induced papulopustular (acneiform) rash on the face.

Figure 25.2. Algorithm for the management of papulopustular (acneiform) rash. (Adapted from Balagula E, Lacouture ME. Dermatologic toxicities. In: Olver IN, ed. The MASCC Textbook of Cancer Supportive Care and Survivorship. New York, NY: Springer; 2011:361-380.)

Hand-Foot Syndrome (HFS)

HFS encompasses reactions related to different groups of anticancer therapies. Conventional chemotherapies, including antimetabolites and anthracyclines, produce the reaction known as palmoplantar erythrodysesthesia (PPE) or HFS, while the multikinase inhibitors (MKIs) are associated with a distinct hand-foot skin reaction (HFSR). Hand-foot reactions may also be seen in patients treated with taxanes; however, in this section we will focus on the former two. HFS from conventional chemotherapies occurs frequently in patients treated with capecitabine, 5-fluorouracil (particularly with continuous infusion), doxorubicin or PEGylated doxorubicin (PLD), cytarabine, methotrexate, and docetaxel. HFS is a condition associated with pain, swelling, numbness, tingling, or redness of the hands or feet (20), with progression to blistering and skin desquamation. The predilection for the palms and soles is thought to be due to drug transport to the skin’s surface via the vasculature and high proliferation of keratinocytes (21,22). Patients are instructed to avoid warm water bathing, tight restrictive clothing or shoes, and vigorous activities such as running (Table 25.2). Pharmacologic agents have some benefit in the prevention of HFS. The COX-2 inhibitor, celecoxib, at a dose of 200 mg/m² twice daily, has been shown to reduce the incidence of overall and high-grade HFS from capecitabine-based chemotherapy (23). Pyridoxine (vitamin B₆) has demonstrated negative results in patients treated with PLD, capecitabine, and continuous 5-fluorouracil infusion (24,25,26). Symptomatic management may include topical moisturizers/keratolytics for low-grade HFS and topical high-potency steroid creams and oral analgesics such as nonsteroidal anti-inflammatory drugs or narcotics for higher grades of HFS. Some patients with HFS from doxorubicin benefit from oral dexamethasone therapy for CTCAE grades ≥2.

TABLE 25.2 Preventative strategies for dermatologic toxicities of targeted anticancer therapies

Papulopustular Rash	Hand-Foot Syndrome/Hand-Foot Skin Reaction	Xerosis/Pruritus	Nail/Periungual Toxicities
Broad-spectrum (UVA/UVB) sunscreen with SPF ≥ 15	Wear thick cotton gloves/socks and shoes with padded insoles	Minimize the frequency and duration of hot showers or baths	Avoid wearing tight-fitting shoes
Physical blockers (zinc oxide, titanium dioxide)	Avoid trauma/friction to hands/feet	Use lukewarm water to shower and wash dishes	Keep nails short
Limit excessive sun exposure	Avoid hot water when bathing or dish washing	Eliminate the use of alcohol-containing products	Avoid hot water when bathing or dish washing
Alcohol-free emollients to moisturize dry skin twice a day	Moisturize with creams containing keratolytics (ammonium lactate or urea)	Alcohol-free emollients to moisturize dry skin twice a day	Moisturize periungual areas
UVA, ultraviolet light A; UVB, ultraviolet light B; SPF, sun protection factor.

HFSR is the most common dose-limiting side effect of the targeted MKIs sorafenib and sunitinib. These two drugs have become first-line therapy for advanced renal cell carcinoma; however, their use in multiple clinical trials is limited by severe and debilitating HFSR. Clinically, patients with HFSR present within the first 2 to 4 weeks of treatment with tender, scaly lesions with surrounding erythema localized to areas of pressure or friction including the tips of fingers and toes, heels, and metatarsophalangeal joints (27). Lesions progress to thickened, hyperkeratotic, painful skin that impairs function and movement (27) (Fig. 25.3). The condition appears to be dose-dependent and typically subsides within several weeks after treatment discontinuation (20). The incidence of all-grade HFSR from sorafenib and sunitinib is 33.8% and 18.9%, respectively (28,29). A newer MKI, pazopanib, shares a similar spectrum of target receptors to sorafenib and sunitinib but is associated with a much lower incidence of HRSF with an all-grade incidence of 4.5% (30). HFSR differs both clinically and mechanistically from classical HFS. One study failed to show any significant levels of sorafenib in the sweat collected from patients’ palms (31). HFSR may be the result of the combined inhibition of vascular endothelial growth factor receptor and platelet-derived growth factor receptor that potentially prevents proper functioning of vascular repair mechanisms leading to drug leakage from capillaries damaged by subclinical trauma (27,31). Preventative measures are similar to those implemented for HFS and are most important during the first 2 to 4 weeks of treatment (Table 25.2). They include the avoidance of vigorous activity and tight-fitting
shoes. Gel soles and hand gloves are also recommended to protect the skin’s integrity and prevent microinjuries at the fingertips and toes that exacerbate HFSR (32). Urea 10% was shown to decrease HFSR severity by sorafenib (33). Treatment recommendations are based on the CTCAE v4.0 grades for PPE (Fig. 25.4).

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