Dermatologic Toxicities of Anticancer Therapy

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. Although pharmacologic intervention has been helpful to aid in hair regrowth, hair follicles cannot be regenerated if they are destroyed. The hair follicle cycles through three phases: growth phase (anagen), a short involuting and 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. 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. 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 ). 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, because CIA does not develop in mice lacking p53 when they are treated with cyclophosphamide. Fas and c-kit have also been implicated. 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. Because the permanent pool of stem cells in the follicle is unaffected by most chemotherapy agents, CIA is typically reversible.

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 or 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 and telogen hair phases is approximately 3 to 4 months. Agents that frequently lead to telogen effluvium include methotrexate, 5-fluorouracil (5-FU), and retinoids. The remainder of this section discusses anagen effluvium–type CIA.

Permanent alopecia, although rare, can occur. In a retrospective review of 8430 patients, seven patients had permanent CIA. Two of these patients were treated with busulphan, and five patients were treated with taxanes.

Epidemiology

The incidence of CIA is unclear, given the lack of standardized grading scales or large epidemiologic studies. 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). In addition to the cytotoxic agent, the risk of CIA also depends on the drug route, dose, and frequency of administration. For example, high-dose, intermittent, intravenous, and combination chemotherapy regimens are more likely to induce alopecia than are low-dose single agents. Several single-nucleotide polymorphisms have been associated with CIA, suggesting a genetic predisposition in certain populations.

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. Anagen effluvium typically begins within days to weeks after initial drug exposure and worsens during the next 1 to 2 months. 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 lost and can manifest with diffuse, patchy, or complete hair loss. Although the vertex (top) of the scalp is the most common site for hair loss, Yun and Kim 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%).

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. Yeager and Olsen 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. 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. Although most QoL studies have focused on women receiving chemotherapy for breast cancer, recent studies have suggested 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. In fact, an equal number of male patients were found to be receptive to paying increased fees to receive a chemotherapy regimen that would reduce their risk of experiencing CIA.

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 41.2 ), and other scales exist as well.

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 a psychiatrist is recommended.

Differential Diagnosis

Telogen effluvium, as previously described, is caused by significant emotional or physical stress, including high fever, surgery, loss of a loved one, and nutritional deficiencies, as well as by many medications, including some chemotherapy agents (e.g., methotrexate). Telogen effluvium is first noticeable about 3 to 6 months after the inciting agent has been administered and is temporary. The incidence of telogen effluvium–type CIA is unclear, but it is thought to occur less commonly than anagen effluvium–type CIA.

Androgenetic alopecia (or “male-pattern” alopecia) typically manifests as gradual hair thinning at the crown and vertex of the scalp. It would not normally occur in the setting of cancer drug administration; however, patients with a predisposition toward androgenetic alopecia may experience CIA in locations similar to that of androgenetic alopecia.

As permanent hair loss can also be experienced secondary to chemotherapeutic agents, it is an important consideration for those experiencing hair loss or incomplete hair regrowth lasting longer than 6 months after the cessation of treatment.

Treatment

Prognosis

Because chemotherapy effects spare the quiescent stem cells in the hair bulge of follicles, cytotoxic CIA is completely reversible in most cases. The hair follicle resumes normal cycling within a few weeks of treatment cessation, and regrowth becomes apparent 1 to 6 months after withdrawal of the offending medication and may even occur during prolonged cycles of therapy. Many patients report a change in the texture, thickness, or color of the new hair. These alterations may affect up to 60% of patients. Hence appropriate counseling of patients who are being treated with these agents may be warranted.

Etiology and Biocharacteristics

Extravasation injury occurs as local tissue injury and necrosis from accidental chemotherapy extravasation in surrounding tissues. Nitrogen mustard, doxorubicin, and related anthracyclines were among the first agents reported to cause surrounding soft tissue necrosis and irritation, in the 1970s. Intravenously administered drugs can be classified into five categories according to their damage potential: vesicants, exfoliants, irritants, inflammitants, and neutrals, which are described in more detail later ( Table 41.3 ).

Epidemiology

The true incidence of chemotherapy extravasation is unknown. The incidence of intravenous, vesicant chemotherapy extravasation is estimated to be 1% to 6%. The concentration, type, and amount of vesicant, as well as the location of extravasation, can all influence the degree of resultant tissue necrosis. 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.

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 five reactions ( Figs. 41.1 and 41.2 ). Vesicants result in tissue necrosis or formation of blisters when accidentally infused into tissue surrounding a vein. Vesicant agents are further divided into DNA-binding and non–DNA-binding categories. DNA-binding agents (e.g., mechlorethamine, doxorubicin, and mitomycin C) bind to DNA in healthy cells, initiating necrosis through cell death. Adjacent cells take up complexes of DNA-bound drug via endocytosis, causing cell necrosis in nearby cells. Non–DNA-binding drugs (e.g., vinblastine, vincristine, and paclitaxel) cause irritation but tend to cause less severe effects.

Exfoliants cause inflammation and shedding of skin without causing underlying tissue death. They may cause superficial tissue injury, blisters, and desquamation. Irritants cause inflammation, pain, or irritation at the extravasation site, without any blister formation. Irritant-type chemotherapy agents are not directly toxic to the tissue, with clinical symptoms thought to be related to the inflammatory response. Inflammitants cause mild to moderate inflammation, painless skin erythema, and elevation (flare reaction) at the extravasation site. Neutrals cause neither inflammation nor damage with extravasation.

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. 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.

Prognosis

The morbidity associated with extravasation injury is high, but mortality is rare. Intravenous vesicant chemotherapeutic agents can cause severe damage to local tissue, leading to possible tissue necrosis, which can result in chronic damage such as scarring. In contrast, irritant drugs cause inflammatory reactions with rare long-term sequelae.

The degree of discomfort experienced by some patients is severe enough to cause voluntary termination of treatment, and the risk of extravasation injury should be discussed before initiation of therapy. The impairment accompanying extravasation injury has no effect on disease status, and thus there is no reason to stop further treatments with a given agent. Unless extravasation occurs again, retreatment of the patient with the same agent is not associated with recurrence of necrosis.

Etiology and Biocharacteristics

Increased pigmentation from cancer chemotherapy is due to increased deposition of melanin in the affected tissue rather than an accumulation of the drug or its byproducts in the skin. Melanin, a pigment product or polymer, is produced within the basal layer of the epidermis of skin, nails, and hair follicles by melanocytes. Melanocytes package the pigment into melanosomes and distribute them to neighboring epithelial cells via dendritic processes. Alterations in baseline pigmentation can occur when there is an increase in melanin production, an increase in the size of melanosomes, or a change in the distribution of melanosomes within the epithelial cells of skin, nails, and hair. How chemotherapeutic agents act to produce increased melanin deposition is unknown. They may increase pigmentation by a direct stimulatory or toxic effect on melanocytes and/or by slowing the turnover and transit rates of epithelial cells, thus allowing more time for the transfer of melanin to occur. Other proposed theories for chemotherapy-induced hyperpigmentation have implicated adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone. However, no elevations of these hormones were noted in studies evaluating the role of ACTH and melanocyte-stimulating hormone in patients with chemotherapy-induced pigment abnormalities.

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-FU. 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.

Clinical Manifestations

Please see Fig. 41.3 and refer to Table 41.5 for specific hyperpigmentation changes related to chemotherapeutic agents.

Workup

No laboratory or imaging studies are necessary, because chemotherapy-induced hyperpigmentation is diagnosed clinically.

Differential Diagnosis

Treatment

Because chemotherapy-induced hyperpigmentation results from increased melanin deposition, therapies targeting melanin may be useful. An RCT found that a combination of nicotinamide and N -acetylglucosamine (NAG) applied daily over a period of 10 weeks resulted in significantly decreased facial hyperpigmentation than the vehicle control formulation. Another vehicle-controlled randomized trial found a combination of niacinamide and tranexamic acid applied twice daily over 8 weeks resulted in significantly decreased facial hyperpigmentation.

Prognosis

Hyperpigmentation as a result of the use of cytotoxic agents is primarily a cosmetic problem and should not affect treatment regimens. Although some patients might experience psychological distress, they can be reassured that cutaneous hyperpigmentation, which may persist for several months, usually resolves after cessation of treatment. Nail pigmentation also resolves as the nails grow after treatment is discontinued.

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 hand-foot syndrome 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. 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 analogues (e.g., capecitabine, cytarabine, and 5-FU), anthracyclines (pegylated liposomal doxorubicin more than doxorubicin), and taxanes (e.g., docetaxel). Less commonly reported causative agents include paclitaxel, hydroxyurea, methotrexate, 6-mercaptopurine, cyclophosphamide, cisplatin, daunorubicin, etoposide, vinorelbine, irinotecan, epirubicin, 6-thioguanine, and tegafur.

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

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. 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. In persons with this condition, symptoms were dose limiting in 30% of patients.

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). Although unconfirmed, patient-specific risk factors have been reported to include the occurrence of mucositis, neutropenia, and peripheral neuropathy.