Dermatologic Toxicity

Susan K. Ailor

Stacia C. Miles

The ability of human skin to serve as a protector, a sensor, a temperature regulator, and an overall window into the body’s ever-changing states is amazing. The skin’s reactions are as diverse as its functions because they can be induced by internal or external stimuli and present with such varied patterns. These patterns reflect both the type of inflammatory cell involved as well as the status of each unique patient.

With the continued expansion of new and promising chemotherapeutic agents, including epidermal growth factor receptor (EGFR) inhibitors and multikinase inhibitors, comes the difficulty of recognizing and managing their complications. This is particularly true with regard to the skin, hair, nails, and mucous membranes. The unique ability of the skin to proliferate and repair itself rapidly makes it a common incidental target for chemotherapeutic drugs. The diagnosis of cutaneous reactions is often complicated in cancer patients who suffer from comorbidities, require multidrug regimens, and are immunosuppressed. Despite this complexity in diagnosis and the wide range of cutaneous presentations, it is important to be aware of the most common skin reactions seen in patients undergoing chemotherapy. Because skin reactions can range from benign to life threatening, the presence of a cutaneous complication does not necessarily require cessation of the drug. Recognizing, monitoring, and addressing cutaneous reactions are a pivotal part of the medical, pharmacologic, and psychological care of the chemotherapy patient. This chapter will discuss the major cutaneous reaction patterns seen in patients undergoing chemotherapy and pinpoint the primary offenders for each pattern.¹ Toxicity grading will utilize the National Cancer Institute unless otherwise noted (Table 13-1).

PAPULOPUSTULAR DERMATITIS

Papulopustular dermatitis, also termed acneiform eruption, xerosis, and paronychia, are the more common dermatologic toxicities of the EGFR inhibitors. Hair abnormalities, including trichomegaly and alopecia, are less common (Table 13-2).

This dermatitis usually begins in 7 to 10 days after beginning therapy but as late as 6 weeks, with increasing activity usually by week 2. Described as pruritic, burning, or stinging, the areas involved favor the seborrheic region. The usual distribution, therefore, includes the scalp, face, neck, postauricular region, shoulders, and upper back. The abdomen, extremities, and lower back are rarely involved. The EGFR is present on epidermal keratinocytes, sebaceous and eccrine glands, and hair follicle epithelium. The dermatitis, which lacks comedones, has a mixed inflammatory perifollicular infiltrate with follicular rupture and epithelial acantholysis.⁴

Grade 3 and grade 4 reactions are seen in 5% to 38% of patients. More frequent and more severe skin toxicity relates to higher dosing and greater response with increased survival in patients.⁷

Treatment response for this rash is often anecdotal. These authors, like others, have had varying, but most often positive, response with the use of doxycycline or minocycline and topical clindamycin and metronidazole. Antihistamines can benefit both inflammation and pruritic complaints. The determination of a treatment regimen depends upon severity of rash, other medications, Fitzpatrick skin type, and patient concern.

STOMATITIS

Most Frequent Offenders

Cytarabine

Fluorouracil

Leucovorin

Methotrexate

Stomatitis, also known as oral mucositis, is the most frequently reported side effect of chemotherapy and radiation in cancer treatment. Although any mucosal surface can be affected by chemotherapy, the oral mucosa, and especially the buccal mucosa and tongue, are the sites most often affected (Fig. 13.1).⁸ Stomatitis influences many patients’ daily functioning, nutrition, and quality of life. The tissue damage from stomatitis results in increased numbers of infections as well as delays and dose reductions of chemotherapy. Although myelosuppression is most often thought of as the major treatment limiting side effect, mucositis may be as well. For example, capecitabine has caused severe mucositis when used in treatment for metastatic breast cancer, resulting in treatment-limiting stomatitis.⁹

Chemotherapeutic agents play a causative role in stomatitis through both direct and indirect mechanisms. The direct mechanism involves drug-induced cytotoxic effects. The same chemotherapeutic agents that are able to destroy cancer cells at a faster rate and higher proportion than most normal healthy cells are also particularly toxic to the rapidly dividing cells of the oral mucosa. Although the epithelium was traditionally the layer of the mucosa recognized as being most damaged by these agents, recent studies have focused on the endothelium,
extracellular matrix, and connective tissue.¹⁰ Mucosal destruction generally appears 4 to 7 days after the initiation of chemotherapeutic agents.¹¹ It is characterized initially by a burning sensation and increased erythema, followed by erosions, ulcerations, and xerostomia.⁸ Healing follows approximately 2 to 3 weeks after the causative drug is discontinued, unless complicated by infection or additional cytotoxic agents.¹¹ This direct form of stomatitis is most noted with the S-phase specific drugs such as fluorouracil, methotrexate, and cytarabine.¹² Younger patients are seen to have more frequent and severe drug-induced cytotoxic effects, given their overall higher rate of mitotic activity compared with elderly patients.

Table 13-1 Major Cutaneous Reaction Patterns Associated with Chemotherapy¹^,²^,³^,⁴^,⁵

Papulopustular dermatitis

Stomatitis

Alopecia

Acral erythema

Radiation recall

Radiation enhancement

Photosensitivity

Neutrophilic dermatoses

Hyperpigmentation

Nail changes

Hypersensitivity

Table 13-2 Papulopustular Dermatitis

Drug	Cases (%)
Cetuximab²	75-91
Erlotinib^2,6	48-75
Everolimus⁶	Approximately 3
Gefitinib^2,6	Up to 80 (43-54)
Panitumumab³	57

The indirect mechanism for stomatitis is characterized by the appearance of significant oral infections secondary to myelosuppression from chemotherapy. These infections generally develop 10 to 21 days after the administration of the drug, which corresponds to the time of the neutrophil nadir, and are most commonly due to gram-negative bacteria and fungi.¹¹^,¹² Although these oral infections are painful and difficult to manage in and of themselves, they also pose a greater risk of resultant septicemia in the neutropenic patient.

Figure 13.1 Stomatitis. (From Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2007.)

Stomatitis occurs in at least 40% of patients undergoing chemotherapy, although other factors such as age, nutrition, type of cancer, concurrent therapies, and oral hygiene have been found to affect the severity and the rate of occurrence.¹¹^,¹³ In fluorouracil-induced stomatitis, the sex of the patient is important as well. In a study of 1,219 patients, the female to male ratio for stomatitis was 63%:52%. Furthermore, grade 3 and 4 stomatitis was seen at a female to male ratio of 22%:12%.¹⁴ Maintaining a stringent regimen of oral health and hygiene has been found to decrease the incidence of stomatitis from approximately 44% to 26%.¹³ Patients who undergo chemotherapy and bone marrow transplantation are particularly vulnerable to both mechanisms causing stomatitis, and have a rate of approximately 76%, whereas those receiving localized radiation in addition to chemotherapy approach a rate of 90%.¹² Within the pediatric population, stomatitis is a particularly concerning development as 2% to 19% of bone marrow recipients who develop stomatitis will eventually develop a related compromise of the airway.¹⁵ Stomatitis may have an overall prognostic significance as well, as the degree of oral mucositis is often a predictor of the severity of subsequent gastrointestinal mucositis and hepatic venocclusive disease (Table 13-3).

ALOPECIA

Most Severe Offenders

Cyclophosphamide	Ixabepilone⁶
Daunorubicin	Paclitaxel
Doxorubicin	Vinblastine
Etoposide	Vincristine
Ifosfamide

One of the most common signs of chemotherapy is alopecia. For many patients, this is a traumatic event as the visible
and public change in appearance affects self-image. Although chemotherapy-induced hair loss is usually a temporary state, surveys of patients undergoing chemotherapy have shown that hair loss was consistently ranked as one of the top three most troubling side effects.¹⁶^,¹⁷

Table 13-3 Chemotherapeutic Agents Associated with Stomatitis

Bevacizumab⁶	5-FU	Mitoxantrone
Bleomycin	Floxuridine	Oxaliplatin
Busulfan	Fludarabine	Paclitaxel
Capecitabine	Gemcitabine (dosedependent)	Pemetrexed
Cetuximab³	Hydroxyurea	Pentostatin⁶
Cyclophosphamide	Idarubicin	Procarbazine
Cytarabine	IL-2	Sorafenib^2,3
Dactinomycin	Interferon γ	Sunitinib^2,3
Dasatinib²	Ixabepilone⁶	Tegafur
Daunorubicin	Leucovorin⁶	Temsirolimus⁶
Decitabine⁶	Levamisole	Teniposide⁶
Dexrazoxane	Lomustine⁶	Topotecan⁶
Docetaxel	Mechlorethamine	Thioguanine⁶
Doxorubicin	Melphalan	Trimetrexate
Doxorubicin, liposomal	Mercaptopurine	Vinblastine
Epirubicin	Methotrexate	Vincristine <1%
Etoposide	Mithromycin	Vinorelbine
IL-2, interleukin 2.

Chemotherapy-induced alopecia occurs as a result of disruption of the normal hair cycle. Human hair cycles through three phases: anagen (growth phase), catagen (transition phase), and telogen (rest phase). The bulk of the mitotic activity of the hair occurs in the bulb where cells proliferate rapidly and are capable of differentiating into the mature cuticle, cortex, and medulla of a hair shaft. At any given time, 85% of hair on the human scalp is in this growth phase or anagen.¹⁸ When an antimitotic chemotherapeutic agent is initiated, the abrupt cessation of mitotic activity in rapidly dividing hair matrix cells causes the hair shaft to thin and break at the surface of the skin. The resulting alopecia is termed as anagen effluvium.¹⁹ In general, anagen effluvium typically starts in the first few days to weeks after the chemotherapy. The degree, timing, and impact of hair loss depend on the agent given, its half-life, dose, schedule, and route of administration.

It has been shown, for example, that taxanes in lower doses given once weekly cause a less severe alopecia than taxanes given in higher doses every third week.²⁰ Docetaxel’s course is unique with hair loss being sudden and complete, usually during the third week after a patient’s first 1-hour infusion.²¹

Although chemotherapy-induced alopecia primarily affects scalp hairs, other sites such as face, arms, legs, and groin may be involved. Fortunately, however, the process is usually reversible with cessation of the agent and most patients show regrowth after 3 to 4 months.²² Regrowth can occur because chemotherapy usually spares the stem cells in the hair follicle bulb. A notable exception to this is busulfan, which has been reported to induce a permanent alopecia by destruction of the lower hair follicle region.²³ Interestingly, because 15% of scalp hairs are not in anagen at any given time, these hairs may escape the effects of chemotherapy, which results in clinically patchy, incomplete patterns of hair loss (Table 13-4).

ACRAL ERYTHEMA

Most frequent offenders

Bleomycin	Doxorubicin, liposomal
Capecitabine	Fluorouracil
Cytarabine	Sorafenib²
Docetaxel	Tegafur

Acral erythema, also called palmar-plantar erythrodysesthesia syndrome and toxic erythema of the palms and soles, was first reported by Zuehlkes in 1974.²⁴ Since that first report about mitotane, the list of caused agents has grown considerably. Reports of incidence run from 0% to 57%.²⁵ Initially thought to be primarily an adult disease, reporting of childhood cases has also increased.²⁶

The effects appear to be dose related, with both total cumulative and peak drug levels contributing.²⁷ A bullous variant has been reported, which results in full thickness epidermal necrosis, from both cytarabine²⁸ and methotrexate.²⁹ Although the cause of acral erythema is uncertain, a direct toxic effect is suggested, with the chemotherapy drug concentrating in the acral area.²⁷ When vinorelbine was studied, 4 of 46 patients developed acral erythema. If the dose was at 10 to 14 mg/m²/day, acral erythema was present; if it was <10 mg/m²/day, it was not.³⁰

The formulation of the drug also plays a role. With liposome-encapsulated doxorubicin, occasionally severe and doselimiting acral erythema appears in up to 51% of patients.³¹ The liposome formation prohibits excretion of the drug by preventing the binding of drug to the plasma proteins. Its coating, a hydrophilic polyethylene glycol, prevents its uptake by the reticuloendothelial system.³²

The mode of administration also plays a role. 5-Fluorouracil (5-FU) given as a bolus has a very low occurrence rate of acral erythema: with a continuous regimen, it is much higher.²⁵ The duration of acral erythema can influence appearance at times. A palmar-plantar keratoderma results when tegafur’s acral erythema becomes chronic.³³

Biopsies show a nonspecific pattern. Findings include mild spongiosis of the epidermis, vacuolar degeneration of the basal
layer, scattered necrotic and dyskeratotic keratinocytes, and mild-to-moderate epidermal atypia with nuclear pleomorphism, multinucleation, and cellular enlargement.²⁷ Discontinuation of the offending drug will usually resolve this reaction. Reducing the dose or changing the timing or type of delivery can be beneficial as well. The form of acral erythema seen with multikinase inhibitors is a localized variant, with both bullous and hyperkeratotic forms seen. Involved sites are those with increased pressure and friction with onset usually in the first 2 weeks of therapy but within 6 weeks²^,³ (Table 13-5).

Table 13-4 Chemotherapeutic Agents Associated with Alopecia

Infrequent to Mild Offenders			Moderate to Severe Offenders
Bleomycin	Fludarabine phosphate	Mitoxantrone	Busulfan^a	Mechlorethamine
Cabazitaxel	Fluorouracil	Nilotinib²	Capecitabine	Methotrexate
Carmustine	Gemcitabine	Panitumumab²	Cyclophosphamide	Mitomycin
Chlorambucil	Hydroxyurea	Sargramostim	Dactinomycin	Paclitaxel
Cisplatin	Idarubicin	Streptozocin	Daunorubicin	Sorafenib³
Cytarabine	Imatinib	Sunitinib³	Docetaxel	Topotecan
Dacarbazine	Interferon α	Teniposide	Doxorubicin	Vinblastine
Daunorubicin, liposomal	Ketoconazole	Thioguanine	Epiubicin	Vincristine
Decitabine	l-Asparaginase	Thiotepa	Etoposide
Dexrazoxane	Letrozole	Vinorelbine	Floxuridine
Doxorubicin, liposomal	Levamisole	Vorinostat	Irinotecan
Erlotinib	Medroxyprogesterone	Zoledronic acid	Ifosfamide
Exemestane	Melphalan		Ixabepilone
Filgrastim	Mercaptopurine
^aModerate offender but alopecia may be permanent. From Tosti A, Piraccini BM, Vincenzi C, et al. Permanent alopecia after busulfan chemotherapy. Br J Dermatol. 2005;152(5):1056-1058.

Table 13-5 Acral Erythema

Bleomycin	Hydroxyurea
Capecitabine	Idarubicin
Cisplatin	Ixabepilone⁶
Cytarabine	Mercatopurine
Dasatinib²	Methotrexate
Daunorubicin, liposomal	Oxaliplatin
Docetaxel	Sorafenib^2,3
Doxorubicin, liposomal	Sunitinib^2,3
Etoposide	Tegafur
Everolimus⁶	Thiotepa
Fluorouracil	Vinorelbine

ADVERSE EFFECTS OF RADIATION

Most Common RR and RE Offenders	Most Common Photosensitivity Offenders
Doxorubicin	Fluorouracil
Dactinomycin	Dacarbazine
	Tegafur
	Vinblastine
RR, radiation recall; RE, radiation enhancement.¹

Radiation therapy is a major component of the curative and palliative treatment for cancer. Measured in grays (Gy), with 1 Gy equivalent to 100 rad, its optimal dosage may be altered by a drug’s chemotherapeutic side effect of radiation enhancement. The synergistic action between the drug and radiation is often desired as an antitumor effect but is problematic when it affects the skin. Radiation recall occurs when a chemotherapy drug causes an inflammatory response in skin that has been previously irradiated, whereas radiation enhancement exists when a drug increases the radiation therapy toxicity. The involved drug and radiation are normally given within a week of each other for enhancement.²⁷^,³⁴ Radiation-induced alopecia within the treatment ports is also
accelerated. Although the mechanism of action has not been determined for most drugs, the vinca alkaloids (vinblastine, vincristine, and vinorelbine) appear to cause cells to stop in the G2/M-phase of the cell cycle where they are more susceptible to radiation-induced apoptosis.³⁴

Table 13-6 Radiation Effect Summary

Drug	Radiation Recall	Radiation Enhancement	UV
Bleomycin	X	X	—
Capecitabine	X	—	—
Cetuximab^3,6	—	X	—
Cyclophosphamide	X	—	X
Cytarabine	X	—	—
Dacarbazine	X	—	—
Dactinomycin	X	—	—
Dasatinib^2,3	—	—	X
Daunorubicin	X	X	—
Docetaxel	X	—	X
Doxorubicin, liposomal	X	X	—
Edatrexate	X	—	—
Epirubicin	X	—	X
Erlotinib^3,6	—	X	—
Etoposide	X	—	X
Fluorouracil	X	—	X
Flutamide	—	—	X
Gemcitabine	X	X	—
Imatinib³	—	—	X, rare
Ixabepilone⁶	X	—	—
Lomustine	X	—	—
Methotrexate	X	—	X
Mitomycin	—	—	X
Oxaliplatin	X	—	—
Paclitaxel	X	—	—
Paclitaxel, protein bound	X	—	—
Panitumumab³	—	X	—
Simvastin	X	—	—
Sunitinib^2,3	—	—	X
Tamoxifen	X	—	—
Tegafur	—	—	X
Thioguanine	—	—	X
Trimetrexate	X	—	—
Vinblastine	X	—	X
X, reported.